CN106220623A - Compounds and methods for and indication thereof for kinases regulation - Google Patents

Compounds and methods for and indication thereof for kinases regulation Download PDF

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CN106220623A
CN106220623A CN201610569522.2A CN201610569522A CN106220623A CN 106220623 A CN106220623 A CN 106220623A CN 201610569522 A CN201610569522 A CN 201610569522A CN 106220623 A CN106220623 A CN 106220623A
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methyl
pyridine
pyridin
base
pyrrolo
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J·张
P·N·阿布拉汉姆
R·布瑞默
W·斯皮瓦克
H·周
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Plexxikon Inc
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Abstract

Describe compound and salt, its preparation, its conjugates, its derivant, its form and its purposes.In some aspects with in embodiment, the compound or its salt of description, its preparation, its conjugates, its derivant, its form are to Fms protein kinase or to Fms and Kit protein kinase or active to Fms and Flt 3 protein kinase.Also describe use its treatment disease and method of disease, described disease or disease include and Fms protein kinase, disease that the activity of Kit protein kinase or Flt 3 protein kinase is relevant or disease, it includes rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer, parkinson, glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, diabetic nephropathy, renal hypertrophy, acute myeloid leukemia, melanoma, multiple myeloma, metastatic breast cancer, carcinoma of prostate, neurofibromatosis, brain metastes and gastrointestinal stromal tumor.

Description

Compounds and methods for and indication thereof for kinases regulation
The application is divisional application, the filing date of original application November 4, Application No. 201080060838.X in 2010 (PCT/US2010/055519), invention entitled " for Compounds and methods for and the indication thereof of kinases regulation ".
Invention field
Disclose compounds and application thereof.In some embodiments, disclosed compound is Fms kinase inhibition Agent.In some embodiments, disclosed compound is Fms and Kit inhibitors of kinases.In some embodiments, disclosed Compound is Fms and Flt-3 inhibitors of kinases.
Summary of the invention
In some aspect disclosed herein and embodiment, it is provided that compound and various salt thereof, its preparation, it is conjugated Thing, its derivant, its form and application thereof.The Formulas I that in some embodiments, compound is discussed further below ', Formulas I, Formula II ', Formula II, Formula II a, formula III ' or the compound of formula III.In some embodiments, this compounds swashs relative to other albumen Enzyme includes that Kit and Flt-3 protein kinase optionally suppresses Fms protein kinase.In some embodiments, such Compound suppression Fms protein kinase and Kit protein kinase.In some embodiments, this compounds suppression Fms protein kinase With Flt-3 protein kinase.In some embodiments, this compounds suppression Fms protein kinase, Kit protein kinase and Flt-3 Each of in protein kinase.
According to the present invention simultaneously it is considered that use this compounds for treating and Fms protein kinase, Kit protein kinase and Any one in Flt-3 protein kinase include the relevant disease of the Active Regulation of these kinase whose any sudden changes and The method of disease (condition).It thus provides compound is for relating to the purposes of the Therapeutic Method of protein kinase regulation. In some embodiments, this compounds be used for relating to Fms kinases, Fms and Kit kinases, Fms and Flt-3 kinases or Fms, Kit and Flt-3 kinases regulation Therapeutic Method, including the treatment of various indications, include but not limited to rheumatoid arthritis, Osteoarthritis, osteoporosis, the osteolysis (peri prosthetic osteolysis) of Periprosthetic, systemic sclerosis Disease, demyelinating disease, multiple sclerosis, summer horse figure three syndrome, amyotrophic lateral sclerosis, Alzheimer, handkerchief The gloomy disease of gold, ulcerative colitis, Crohn disease, immunologic thrombocytopenic purpura, atherosclerosis, systematicness erythema Property lupus, autoplastic spinal cord prepare (myelopreparation for autologous transplantation), move Plant rejection, glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, diabetic nephropathy, kidney fertilizer Greatly, type i diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple Myeloma, metastatic breast cancer, carcinoma of prostate, cancer of pancreas, pulmonary carcinoma, ovarian cancer, glioma, glioblastoma multiforme, nerve fiber Tumor, osteolytic Bone tumour, brain metastes, gastrointestinal stromal tumor and giant cell tumor.
The compound of structure in the first aspect, it is provided that have according to following formula I ':
Or its salt, prodrug, tautomer or stereoisomer,
Wherein:
Ar is selected from:
WhereinThe Ar and-CH of expression I '2-junction point and whereinThe junction point of the Ar and-NH-of expression I '；
R1、R2、R3And R4Each takes independently selected from-H, halogen, low-carbon alkyl, the low-carbon alkyl of halogen substiuted, halogen The substituted low-carbon alkyl of the low-carbon alkoxy in generation, alkoxyl, cycloalkyl amino ,-CN ,-O-R40、-S(O)2-R41、-S(O)2-N (H)-R42、-N(H)-R42、-N(R42)2With-N (H)-S (O)2-R43, condition is R1、R2、R3And R4In at least two be-H and R1、R2、R3And R4In a non-hydrogen, wherein:
R40It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；
R41、R42And R43It it is low-carbon alkyl；
R5Selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the alkyl of halogen substiuted, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkanes Base, phenyl, pyrazolyl ,-CN ,-O-R10、-C(O)-N(H)-R11、-C(O)-O-R11、-S(O)2-R12、-S(O)2-N(H)-R11、- N(H)-C(O)-R12With-N (H)-S (O)2-R12, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R6Selected from H, halogen, low-carbon alkyl, the alkyl of halogen substiuted, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, Pyrazolyl ,-CN ,-O-R13、-C(O)-N(H)-R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14、-N(H)-C (O)-R15With-N (H)-S (O)2-R15, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R7It is H, halogen or low-carbon alkyl；
R8It is H, halogen or low-carbon alkoxy；
R9It is H or halogen；
R10And R13Be independently-H, low-carbon alkyl, with-O-CH3Substituted low-carbon alkyl, with the substituted low-carbon (LC) of dialkylamine Alkyl or with the substituted low-carbon alkyl of Heterocyclylalkyl；
R11And R14It is hydrogen or low-carbon alkyl independently；And
R12And R15Each is low-carbon alkyl independently,
Condition be this compound be not in table 1 propose those compounds.
In some embodiments, R1、R3And R4Each is independently selected from-H, low-carbon alkoxy, halogen, halogen substiuted Low-carbon alkyl, the substituted low-carbon alkyl of alkoxyl, cycloalkyl amino ,-CN ,-O-R40、-S(O)2-R41、-S(O)2-N(H)- R42、-N(H)-R42、-N(R42)2With-N (H)-S (O)2-R43, condition is R1、R2、R3And R4In at least two be-H and R2 It is-F ,-Cl or-Br；Or R1、R2And R3It is-H and R4It is-CF3；Or R1And R4It is-H, R2It is-O-CH3, and R3Be- F；Or R2And R4It is-H, R1It is-O-CH3, and R3It is-F；
R5Selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, ring Alkyl, phenyl, pyrazolyl ,-CN ,-O-R10、-C(O)-N(H)-R11、-C(O)-O-R11、-S(O)2-R12、-S(O)2-N(H)- R11、-N(H)-C(O)-R12With-N (H)-S (O)2-R12, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R6Selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, ring Alkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N(H)-R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)- R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R7It is-H ,-F ,-Cl or-CH3；
R8It is-H ,-F ,-CH3Or-O-CH3；
R9It is-H or-Cl；
R10And R13Be independently-H, low-carbon alkyl, with-O-CH3Substituted low-carbon alkyl, with the substituted low-carbon (LC) of dialkylamine Alkyl or with the substituted low-carbon alkyl of Heterocyclylalkyl；
R11And R14It is hydrogen or low-carbon alkyl independently；And
R12And R15It is low-carbon alkyl independently.
In some embodiments, Ar isWherein R7As defined herein.
In some embodiments, Ar isWherein R8As defined herein.
In some embodiments, Ar is
In some embodiments, Ar is
In some embodiments, Ar isWherein R9As defined herein.
In some embodiments, R1、R3And R4It is H and R2It it is halogen.In other embodiments, R1、R2And R3Be- H and R4It it is the substituted low-carbon alkyl of halogen.In other embodiments, R1And R4It is-H and R2It it is low-carbon alkoxy.One In a little embodiments, R3It it is halogen.In other embodiments, R2And R4It is-H, R1It is low-carbon alkoxy and R3It it is halogen.? In some situation, i) R1、R2And R3It is-H and R4It is CF3；Or ii) R1And R4It is-H and R2It is-OCH3；Or iii) R3 It is F；Or iv) R2And R4It is-H, R1It is OCH3And R3It is F.Variable R5、R6With Ar as defined herein.
In Formulas I ' compound some embodiments in, R5It is that-H ,-F ,-Cl ,-Br, low-carbon alkyl, fluorine are substituted low Carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, pyrazolyl ,-CN ,-O-R10、-C(O)-N(H)-R11、-C(O)- O-R11、-S(O)2-R12、-S(O)2-N(H)-R11、-N(H)-C(O)-R12With-N (H)-S (O)2-R12, wherein pyrazolyl is optionally Replaced by low-carbon alkyl or Heterocyclylalkyl.In some cases, R5It is H.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R5It is-H.In some embodiments, R5It is-H and R6Be- H、-F、-Cl、-CH3、-CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、- NHS(O)2CH3Or cyclopropyl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R6Selected from H, halogen (halo), low-carbon alkyl, low-carbon (LC) alcoxyl The substituted low-carbon alkyl of base, fluorine, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N (H)-R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, its Middle pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl.In some cases, R6Being halogen, low-carbon alkyl or fluorine replace Low-carbon alkyl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R6It is-H.In some embodiments, R6It is-H and R5Be- H、-Cl、-CN、-C≡CH、-O-CH3Or phenyl.In other embodiments, R6Be halogen, low-carbon alkyl, low-carbon alkoxy or The substituted low-carbon alkyl of fluorine.In other embodiments, R6It is halogen, methyl, methoxyl group, trifluoromethyl or CN.All other Variable is as defined herein.
In Formulas I ' compound some embodiments in, R7It is H, halogen or low-carbon alkyl.In other embodiments, R7It is H ,-F ,-Cl, Br or-CH3.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R8It is H, halogen or low-carbon alkoxy.At other embodiment In, R8It is H ,-F ,-Cl, Br or-OCH3.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R9It is H or halogen.In other embodiments, R9Be-H or- Cl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；And R5Be- H.In some embodiments, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；R5It is-H；And R6Be-H ,-F ,-Cl ,- CH3、-CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or Cyclopropyl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；And R6Be- H.In some embodiments, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH、-O-CH3Or phenyl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R1、R2And R3It is-H；And R4It is-CF3；And R5It is-H.? In some embodiments, R1、R2And R3It is-H；And R4It is-CF3；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、-CF3、- CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or cyclopropyl.Institute There is other variable as defined herein.
In Formulas I ' compound some embodiments in, R1、R2And R3It is-H；And R4It is-CF3；And R6It is-H.? In some embodiments, R1、R2And R3It is-H；And R4It is-CF3；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH ,-O- CH3Or phenyl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R1And R4It is-H；R2It is-O-CH3；R3It is-F；And R5It is-H. In some embodiments, R1And R4It is-H；R2It is-O-CH3；R3It is-F；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、- CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or ring third Base.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R1And R4It is-H；R2It is-O-CH3；R3It is-F；And R6It is-H. In some embodiments, R1And R4It is-H；R2It is-O-CH3；R3It is-F；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH、-O-CH3Or phenyl.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R2And R4It is-H；R1It is-O-CH3；R3It is-F；And R5It is-H. In some embodiments, R2And R4It is-H；R1It is-O-CH3；R3It is-F；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、- CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or ring third Base.Other variablees all are as defined herein.
In Formulas I ' compound some embodiments in, R2And R4It is-H；R1It is-O-CH3；R3It is-F；And R6It is-H. In some embodiments, R2And R4It is-H；R1It is-O-CH3；R3It is-F；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH、-O-CH3Or phenyl.Other variablees all are as defined herein.
On the other hand, it is provided that there is the compound according to following formula I structure:
Or its salt, prodrug, tautomer or stereoisomer,
Wherein Ar is selected from:
WhereinThe Ar and-CH of expression I2-junction point, whereinThe junction point of the Ar and-NH-of expression I；
R1、R3And R4It is-H and R2It is-F ,-Cl or-Br；Or R1、R2And R3It is-H and R4It is-CF3；Or R1And R4 It is-H, R2It is-O-CH3, and R3It is-F；Or R2And R4It is-H, R1It is-O-CH3, and R3It is-F；
R5Selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, ring Alkyl, phenyl, pyrazolyl ,-CN ,-O-R10、-C(O)-N(H)-R11、-C(O)-O-R11、-S(O)2-R12、-S(O)2-N(H)- R11、-N(H)-C(O)-R12With-N (H)-S (O)2-R12, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R6Selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, ring Alkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N(H)-R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)- R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R7It is-H ,-F ,-Cl or-CH3；
R8It is-H ,-F ,-CH3Or-O-CH3；
R9It is-H or-Cl；
R10And R13Be independently-H, low-carbon alkyl, with-O-CH3Substituted low-carbon alkyl, with the substituted low-carbon (LC) of dialkylamine Alkyl or with the substituted low-carbon alkyl of Heterocyclylalkyl；
R11And R14It is hydrogen or low-carbon alkyl independently；And
R12And R15It is low-carbon alkyl independently.
In some embodiments of the compound of Formulas I, R5It is-H.In some embodiments, R5It is-H and R6Be- H、-F、-Cl、-CH3、-CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、- NHS(O)2CH3Or cyclopropyl.
In some embodiments of the compound of Formulas I, R6It is-H.In some embodiments, R6It is-H and R5Be- H、-Cl、-CN、-C≡CH、-O-CH3Or phenyl.
In some embodiments of the compound of Formulas I, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；And R5It is-H. In some embodiments, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、- CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or ring third Base.
In some embodiments of the compound of Formulas I, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；And R6It is-H. In some embodiments, R1、R3And R4It is-H；R2It is-F ,-Cl or-Br；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH、-O-CH3Or phenyl.
In some embodiments of the compound of Formulas I, R1、R2And R3It is-H；And R4It is-CF3；And R5It is-H.? In some embodiments, R1、R2And R3It is-H；And R4It is-CF3；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、-CF3、- CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or cyclopropyl.
In some embodiments of the compound of Formulas I, R1、R2And R3It is-H；And R4It is-CF3；And R6It is-H.? In some embodiments, R1、R2And R3It is-H；And R4It is-CF3；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH ,-O- CH3Or phenyl.
In some embodiments of the compound of Formulas I, R1And R4It is-H；R2It is-O-CH3；R3It is-F；And R5It is-H. In some embodiments, R1And R4It is-H；R2It is-O-CH3；R3It is-F；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、- CF3、-CN、-O-CH3、-S(O)2-CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or ring third Base.
In some embodiments of the compound of Formulas I, R1And R4It is-H；R2It is-O-CH3；R3It is-F；And R6It is-H. In some embodiments, R1And R4It is-H；R2It is-O-CH3；R3It is-F；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH、-O-CH3Or phenyl.
In some embodiments of the compound of Formulas I, R2It is-H with r4；R1It is-O-CH3；R3It is-F；And R5It is-H. In some embodiments, R2And R4It is-H；R1It is-O-CH3；R3It is-F；R5It is-H；And R6It is-H ,-F ,-Cl ,-CH3、- CF3、-CN、-O-CH3、-S(O)2CH3、-C(O)-NH-CH3、-C(O)-O-CH3、-NHC(O)CH3、-NHS(O)2CH3Or ring third Base.
In some embodiments of the compound of Formulas I, R2And R4It is-H；R1It is-O-CH3；R3It is-F；And R6It is-H. In some embodiments, R2And R4It is-H；R1It is-O-CH3；R3It is-F；R6It is-H；And R5It is-H ,-Cl ,-CN ,-C ≡ CH、-O-CH3Or phenyl.
In an embodiment of Formulas I and the compound of I ', compound is selected from:
[5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-fluoro-2-methoxy Base-pyridin-3-yl methyl)-amine (P-1497), (6-chloro-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1498), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1499), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[fluoro-5-of 6- (1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1500), [6-fluoro-5-(1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1501), (5-fluoro-6-first Epoxide-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1502), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-1403), [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3- Ylmethyl)-amine (P-1504), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-is fluoro- 2-methoxv-pyridine-3-ylmethyl)-amine (P-1505), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1506), (6-chloro-pyridin-3-yl methyl)-[6-is chloro- 5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1508), [the chloro-5-of 6-(1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1509), [6-is chloro- 5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 1510), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-amine (P-1513), (6-chloro-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-phonetic Pyridine-2-base]-amine (P-1515), [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-fluoroform Base-pyridin-3-yl methyl)-amine (P-1516), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1520), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-thiazol-2-yl]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1521), (6-chloro-pyridin-3-yl methyl)- [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1523), [4-chloro-5-(1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P- 1524), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(4-trifluoromethylpyridin-3- Ylmethyl)-amine (P-1525), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1528), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1529), (6-chloro-pyridin-3-yl methyl)- [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1531), (5-fluoro-6-methoxy Base-pyridin-3-yl methyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-1533), (6-chloro-pyridin-3-yl methyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1535), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[6-methyl-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1536), [6-methyl-5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1537), [the chloro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-6-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amine (P-1540), [the chloro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(6-chloro-pyridin-3-yl methyl)-amine (P-1542), [the chloro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1543), [the chloro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 1544), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-1547), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[3-methoxyl group-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1548), (6-chloro-pyridin-3-yl first Base)-[3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1550), [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethyl-pyrrole Pyridine-3-ylmethyl)-amine (P-1551), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1555), (6-chloro-pyridin-3-yl methyl)-[3-methyl- 5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1557), (5-fluoro-2-methoxy Base-pyridin-3-yl methyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-1558), [3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1559), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[fluoro-5-of 3- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1563), (the chloro-pyridin-3-yl of 6- Methyl)-[the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1565), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-1566), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1567), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1570), (5-fluoro-6-methoxv-pyridine- 3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1579), (6- Chloro-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P- 1581), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(4-trifluoromethylpyridin- 3-ylmethyl)-amine (P-1582), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1584), (6-chloro-pyridin-3-yl methyl)-[5-(5-methoxyl group- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1586), (5-fluoro-2-methoxv-pyridine-3-base Methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1587), [5- (5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-1588), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1590), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(6-chloro-pyridin-3-yl methyl)-amine (P-1592), [the chloro-5-of 6-(5-methoxyl group-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P- 1593), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-fluoroform Base-pyridin-3-yl methyl)-amine (P-1594), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1597), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1598), (5-fluoro-2-first Epoxide-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1599), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-amine (P-1600), (6-chloro-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1602), [5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1603), (6-chloro-pyridin-3-yl methyl)- [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-amine (P-1607), [(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1608), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(5-fluoro-6-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amine (P-1611), (6-chloro-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyrimidine-2-base]-amine (P-1612), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1613), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1623), (the chloro-pyridin-3-yl of 6- Methyl)-[the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1625), [6- Fluoro-5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-base Methyl)-amine (P-1626), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4- Trifluoromethylpyridin-3-ylmethyl)-amine (P-1627), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(fluoro-1H-of 5- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1630), (6-chloro-pyridin-3-yl methyl)-[5-(5- Fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1632), (5-fluoro-2-methoxv-pyridine- 3-ylmethyl)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1633), [5- (5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1634), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1638), (6-chloro-pyridin-3-yl methyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1640), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5- (5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1641), (4-trifluoromethyl- Pyridin-3-yl methyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 1642), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-1646), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-Trifluoromethyl-1 H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1648), (5-fluoro-2-methoxv-pyridine-3-Ji Jia Base)-[the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1649), [the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethyl-pyrrole Pyridine-3-ylmethyl)-amine (P-1650), the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridine- 3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1654), 3-{6-[(6-chloro-pyridin-3-yl methyl)-amino]- 2-fluoro-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1655), the fluoro-6-of 3-{2-[(5-fluoro-2-methoxy Base-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1656), 3- { the fluoro-6-of 2-[(4-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyrrole Pyridine-5-nitrile (P-1657), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-is fluoro- 6-methoxv-pyridine-3-ylmethyl)-amine (P-1661), (6-chloro-pyridin-3-yl methyl)-[5-(5-cyclopropyl-1H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1663), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1664), [5-(5-ring third Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 1665), N-(the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrole Cough up also [2,3-b] pyridine-5-base)-acetamide (P-1670), N-(3-{6-[(6-chloro-pyridin-3-yl methyl)-amino]-2- Fluoro-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1672), N-(3-{2-fluoro-6-[(4- Trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetyl Amine (P-1673), N-(the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }- 1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1677), N-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P- 1680), N-(the fluoro-6-of 3-{2-[(4-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo- [2,3-b] pyridine-5-base)-Methanesulfomide (P-1681), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1685), (the chloro-pyridin-3-yl of 6- Methyl)-[the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 1687), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(the fluoro-2-of 5- Methoxv-pyridine-3-ylmethyl)-amine (P-1688), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1689), the fluoro-6-of 3-{2-[(the fluoro-2-of 5- Methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-carboxylate methyl ester (P- 1693), the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo- [2,3-b] pyridine-5-acid methylamide (P-1694), the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-ammonia Base]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1696), 3-{6-[(the chloro-pyrrole of 6- Pyridine-3-ylmethyl)-amino]-2-fluoro-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P- 1697), the fluoro-6-of 3-{2-[(4-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2, 3-b] pyridine-5-acid methylamide (P-1698), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-{ the fluoro-5-of 6-[5-(1-piperazine Pyridine-4-base-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-amine (P-1703), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-{ the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl]-pyridine-2-base-amine (P-1704), (6-chloro-pyridin-3-yl methyl)-{ 6-fluoro-5-[5- (1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-amine (P- 1706), { the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyrrole Pyridine-2-base }-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1707), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1711), (the chloro-pyrrole of 6- Pyridine-3-ylmethyl)-[5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 1713), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxyl group- Pyridin-3-yl methyl)-amine (P-1714), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1715), 3-{6-[(6-chloro-pyridin-3-yl methyl)-amino]-pyrrole Pyridine-3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1720), 3-{6-[(5-fluoro-2-methoxv-pyridine-3-base Methyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1721), 3-{6-[(4-fluoroform Base-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1722), 3- { 6-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine- 4-nitrile (P-1726), (6-bromo-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-amine (P-2002), (6-chloro-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2003), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (6-fluoro-pyridin-3-yl methyl)-amine (P-2004), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[6-fluoro-5-(5-methoxy Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2040), (5-fluoro-6-methoxv-pyridine- 3-ylmethyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2041), (5- Fluoro-2-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2042), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2048), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2049), (5-fluoro-2-first Epoxide-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2061), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-fluoroform Base-pyridin-3-yl methyl)-amine (P-2062), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-2063), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-2064), [5-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-2070), (5- Fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-2073), (6-chloro-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-amine (P-2078), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2088), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-thiazol-2-yl]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-2152), (5-fluoro-2-methoxv-pyridine- 3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-2153), [5- (5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-base Methyl)-amine (P-2165), [5-(4-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(fluoro-2-of 5- Methoxv-pyridine-3-ylmethyl)-amine (P-2170), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(4-phenyl-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2171), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-base) methyl] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl] pyridine-2-amine (P-2203), 3-[[2- Fluoro-6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methylamino]-3-pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5- Nitrile (P-2204), the chloro-N-of 6-[(5-fluoro-2-methoxyl group-3-pyridine radicals) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl) methyl] pyridine-2-amine (P-2205), the fluoro-N-of 6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5- (trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] pyridine-2-amine (P-2206) and its any salt, precursor Medicine, tautomer or stereoisomer.
In some embodiments of the compound of Formulas I and I ', R7Non-hydrogen.Other variablees all are as defined herein.
In one group of embodiment of Formulas I and the compound of I ', R6And R7It is asynchronously H.Other variablees all are as fixed herein Justice.
In another group embodiment of the compound of Formulas I and I ', work as R7When being halogen, R6Be not H, halogen, heteroaryl, CN or low-carbon alkyl.In some cases, R is worked as7When being Cl, R6It not H, Cl, pyrazolyl (pyrrazolyl), CN or CH3.Institute There is other variable as defined herein.
In another group embodiment of the compound of Formulas I and I ', work as R7When being halogen, R6It it not the substituted low-carbon (LC) of halogen Alkyl.In some cases, R is worked as7When being Cl, R6It not CF3.Other variablees all are as defined herein.
In one group of embodiment of Formulas I and the compound of I ', work as R7When being halogen, R2It it not the lower alkanes of halogen substiuted Base or low-carbon alkoxy.In some cases, R is worked as7When being F, R2It not CF3Or-OCH3.Other variablees all are as defined herein.
In another group embodiment of the compound of Formulas I and I ', work as R7When being halogen, R6It not halogen, low-carbon (LC) alcoxyl Base, hydrogen or CN.In some cases, R is worked as7When being-F, R6It not Cl, OCH3, hydrogen or CN.In other situation, work as R7It is-F Time, R3It not F.Other variablees all are as defined herein.
In one group of embodiment of Formulas I and the compound of I ', work as R7When being hydrogen, R6It not halogen, hydrogen, low-carbon alkyl, CN Or low-carbon alkoxy.In some cases, R is worked as7When being hydrogen, R6It not H, Cl, F, CH3、CN、-OCH3.Other variablees all are such as Define herein.
In another group embodiment of the compound of Formulas I and I ', work as R9When being halogen, R6It not H or halogen.At some In situation, work as R9When being Cl, R6It not H or Cl.Other variablees all are as defined herein.
In another group embodiment of the compound of Formulas I and I ', when Ar isTime, R6Non-hydrogen.All other Variable is as defined herein.
In another group embodiment of the compound of Formulas I and I ', when Ar isTime, R1、R2、R3And R4Different Time be hydrogen.Other variablees all are as defined herein.
In another group embodiment of the compound of Formulas I and I ', when Ar isTime, R2It not that halogen is substituted Low-carbon alkyl, such as, in one embodiment, R2It not CF3.Other variablees all are as defined herein.
From Formulas I ' and Formulas I get rid of compound be listed in the table below 1.
Table 1
[the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin- 3-ylmethyl)-amine (P-0174), [the chloro-5-of 6-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0176), { the chloro-5-of 6-[5-(1-methyl isophthalic acid H-pyrazoles-4-base)-1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0179), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(6-trifluoromethylpyridin-3-base Methyl)-amine (P-0186), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0187), [the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0188), the chloro-6-of 3-{2-[(6-trifluoromethyl- Pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-0232), [6-is chloro- 5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-0233), [the chloro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6- Trifluoromethylpyridin-3-ylmethyl)-amine (P-0234), [the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-0378), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-6-fluoro-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-0379), (5-fluoro-pyridin-3-yl first Base)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0414), the fluoro-6-of 3-{2- [(5-fluoro-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-0415), 3-[6-(the chloro-benzylamino of 4-)-2-fluoro-pyridin-3-yl methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-0432), pyrrole Pyridine-3-ylmethyl-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0094), (2-methoxy Base-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0215), (6-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 0219), (5-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-0222), (5-fluoro-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-0230), 3-{6-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrroles And [2,3-b] pyridine-5-nitrile (P-0273), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0282), 3-{6-[(6-methoxv-pyridine-3-ylmethyl)-amino]- Pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-0284), (2-methoxv-pyridine-3-ylmethyl)-[5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0285), [5-(the chloro-1H-pyrroles of 5- And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-0286), 3-{6- [(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P- 0287), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl first Base)-amine (P-0324), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxyl group- Pyridin-3-yl methyl)-amine (P-0331), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0332), (2-morpholine-4-base-pyridin-3-yl methyl)-[5-(1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0347), (2,6-dimethoxy-pyridin-3-Ji Jia Base)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0370), (6-cyclopentyloxy-pyrrole Pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-0374), [5-(1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl methyl]- Amine (P-0376), (5-chloro-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-0400), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-[6-(2,2,2- Trifluoro-ethoxy)-pyridin-3-yl methyl]-amine (P-0409), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0181), [5-(1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0182), [4-chloro-5-(1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-pyridin-3-yl methyl-amine (P-0164), [4-chloro-5-(1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0173), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-pyridin-3-yl methyl-amine (P-0422), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-0429), 2,2-dimethyl-N-(3-{ [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base Amino]-methyl-pyridine-2-base)-propionic acid amide. (P-0384), methyl-(3-{ [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base amino]-methyl-pyridine-2-base)-amine (P-0385), dimethyl-(3-{ [5-(1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-pyridine-2-base)-amine (P-0399), [(5-is chloro-for the chloro-5-of 4- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(3-fluoro-pyridin-4-yl methyl)-amine (P-0200), [4- Chloro-5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-pyridin-3-yl methyl-amine (P- 0236), [the chloro-5-of 4-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(5-methoxv-pyridine- 3-ylmethyl)-amine (P-0241), [the chloro-5-of 4-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]- (6-trifluoromethylpyridin-3-ylmethyl)-amine (P-0242), [the chloro-5-of 4-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-thiazol-2-yl]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-0247) and [4-chloro-5-(1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-thiazol-2-yl]-(5-methoxv-pyridine-3-ylmethyl)-amine (P-0207).
In second aspect, the invention provides and there is Formula II ' compound:
Or its salt, prodrug, tautomer or stereoisomer,
Wherein:
R16、R17、R18And R19Each is substituted low independently selected from H, halogen, low-carbon alkyl, low-carbon alkoxy, halogen The substituted low-carbon alkyl of carbon alkyl, alkoxyl, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-S(O)2-N(H)-R22、-N (H)-R22、-N(R22)2With-N (H)-S (O)2-R23, condition is R16、R17、R18And R19In at least two be-H；
R20It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；R21It it is low-carbon (LC) Alkyl；R22It it is low-carbon alkyl；And R23It it is low-carbon alkyl.
In Formula II ' compound some embodiments in, R6Selected from halogen, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, Low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N(H)-R14、-C(O)-O-R14、-S (O)2-R15、-S(O)2-N(H)-R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, wherein pyrazolyl is optionally by lower alkanes Base or Heterocyclylalkyl replace.In some cases, R6It is F, Cl, Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, low-carbon (LC) alkene Base ,-CN ,-C (O)-N (H)-R14、-N(H)-C(O)-R15、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14Or-N (H)-S(O)2-R15.In other situation, R6It is methyl, ethyl, propyl group, butyl, amyl group or hexyl.Other variablees all are as originally Literary composition definition.
In some embodiments, it is provided that there is the compound according to formula II below structure:
Or its salt, prodrug, tautomer or stereoisomer,
Wherein:
R16、R17、R18And R19Independently selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, methoxyl group Substituted low-carbon alkyl, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-S(O)2-N(H)-R22、-N(H)-R22、-N (R22)2With-N (H)-S (O)2-R23, condition is R16、R17、R18And R19In at least two be-H；
R20It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；
R21It it is low-carbon alkyl；
R22It it is low-carbon alkyl；And
R23It it is low-carbon alkyl.
In some embodiments of the compound of Formula II and II ', R16、R17、R18And R19Each independently selected from-H ,- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R20、-S(O)2-R21、-S(O)2-N(H)-R22、-N(H)-R22、-N(R22)2With-N (H)-S (O)2-R23, condition is R16、R17、R18 And R19In at least two be-H.In some embodiments, R17And R19It is H, halogen or low-carbon alkyl.Other variablees all As defined herein.
In other embodiment of the compound of Formula II and II ', R16、R17、R18And R19Each is independently selected from H, halogen Element, low-carbon alkyl, carbon alkoxyl, the substituted low-carbon alkyl of halogen ,-OR20, or the substituted low-carbon alkyl of alkoxyl, condition is R16、R17、R18And R19In at least two be-H.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II and II ', R16、R17And R18It is H and R19Be-F ,-Cl ,-Br, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2- R21、-N(H)-R22、-N(R22)2, or-N (H)-S (O)2-R23.In some embodiments, R16、R17And R18It is H and R19Be- The substituted low-carbon alkyl of F ,-Cl, low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22Or-N (R22)2.Real at some Execute in mode, R16、R17And R18It is H and R19It is the substituted low-carbon alkyl of fluorine or-O-R20.In some embodiments, R16、R17 And R18It is H and R19It is-CF3Or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II and II ', R16、R17And R19It is H and R18Be-F ,-Cl ,-Br, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2- R21、-N(H)-R22、N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16、R17And R19It is H and R18Be- The substituted low-carbon alkyl of F ,-Cl, low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22Or-N (R22)2.Real at some Execute in mode, R16、R17And R19It is H and R18It is-F ,-Cl or-O-R20.In some embodiments, R16、R17And R19Be H also And R18It is-F ,-Cl or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II and II ', R16、R18And R19It is H and R17Be-F ,-Cl ,-Br, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2- R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16、R18And R19It is H and R17Be- The substituted low-carbon alkyl of F ,-Cl, low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22Or-N (R22)2.Real at some Execute in mode, R16、R18And R19It is H and R17It is-Cl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino or-O-R20.At some In embodiment, R16、R18And R19It is H and R17It is-Cl ,-CF3、-O-CH3Or morpholine-4-base.Other variablees all are as herein Definition.
In some embodiments of the compound of Formula II and II ', R17、R18And R19It is H and R16Be-F ,-Cl ,-Br, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2- R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R17、R18And R19It is H and R16Be- The substituted low-carbon alkyl of F ,-Cl, low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22Or-N (R22)2.Real at some Execute in mode, R17、R18And R19It is H and R16It is-F ,-CF3, morpholine-4-base ,-O-CH3、-O-CH2CH3、-O-CH(CH3)2、- O-CH2CF3,-O-ring amyl group ,-O-ring hexyl or-N (H)-CH3.In some embodiments, R17、R18And R19It is H and R16 It is-F ,-CF3Or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II and II ', R16And R17It is H；And R18And R19Be independently-F ,- The substituted low-carbon alkyl of Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16And R17It is H；And R18With R19It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20Or-N (H)-R22Or-N (R22)2.In some embodiments, R16And R17It is H；And R18And R19It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II and II ', R16And R18It is H；And R17And R19Be independently-F ,- The substituted low-carbon alkyl of Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16And R18It is H；And R17With R19It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20Or-N (H)-R22Or-N (R22)2.In some embodiments, R16And R18It is H；And R17And R19It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R16And R18It is H；And R17And R19It is-CF independently3Or-O-CH3.Other variablees all As defined herein.
In some embodiments of the compound of Formula II and II ', R16And R19It is H；And R17And R18Be independently-F ,- The substituted low-carbon alkyl of Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16And R19It is H；And R17With R18It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20Or-N (H)-R22Or-N (R22)2.In some embodiments, R16And R19It is H；And R17And R18It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R16And R19It is H；And R17And R18It is-F or-O-CH independently3.Other variablees all are such as Define herein.
In some embodiments of the compound of Formula II and II ', R17And R18It is H；And R16And R19Be independently-F ,- The substituted low-carbon alkyl of Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R17And R18It is H；And R16With R19It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R17And R18It is H；And R16And R19It is-F ,-Cl ,-CF independently3、-O-CH3Or-N (CH3)2.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II, R17And R19It is H；And R16And R18Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R17And R19It is H；And R16With R18It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R17And R19It is H；And R16And R18It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R17And R19It is H；And R16And R18It is-F ,-Cl or-O-CH independently3.All other becomes Amount is as defined herein.
In some embodiments of the compound of Formula II and II ', R18And R19It is H；And R16And R17Be independently-F ,- The substituted low-carbon alkyl of Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R18And R19It is H；And R16With R17It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R18And R19It is H；And R16And R17It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R18And R19It is H；And R16And R17It is-CF independently3、-O-CH3Or-N (CH3)2.All Other variable is as defined herein.
In some embodiments, it is provided that there is the compound according to formula II below a structure:
Or its salt, prodrug, tautomer or stereoisomer,
Wherein:
R16、R17、R18And R19Independently selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, methoxyl group Substituted low-carbon alkyl, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-S(O)2-N(H)-R22、-N(H)-R22、-N (R22)2With-N (H)-S (O)2-R23, condition is R16、R17、R18And R19In at least two be-H；
R20It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；
R21It it is low-carbon alkyl；
R22It it is low-carbon alkyl；And
R23It it is low-carbon alkyl.
In some embodiments of the compound of Formula II a, R16、R17、R18And R19Each independently selected from-H ,-F ,- The substituted low-carbon alkyl of Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-S(O)2-N(H)-R22、-N(H)-R22、-N(R22)2With-N (H)-S (O)2-R23, condition is R16、R17、R18And R19 In at least two be-H.In some embodiments, R17And R19It is H, halogen or low-carbon alkyl.Other variablees all are as originally Literary composition definition.
In other embodiment of Formula II a compound, R16、R17、R18And R19Each is independently selected from H, halogen, low The substituted low-carbon alkyl of carbon alkyl, low-carbon alkoxy, halogen ,-OR20, or the substituted low-carbon alkyl of alkoxyl, condition is R16、 R17、R18And R19In at least two be-H.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R16、R17And R18It is H and R19It is-F ,-Cl ,-Br, low-carbon (LC) The substituted low-carbon alkyl of alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-N (H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16、R17And R18It is H and R19Be-F ,-Cl, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、N(H)-R22Or-N (R22)2.At some embodiments In, R16、R17And R18It is H and R19It is the substituted low-carbon alkyl of fluorine or-O-R20.In some embodiments, R16、R17And R18 It is H and R19It is-CF3Or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R16、R17And R19It is H and R18It is-F ,-Cl ,-Br, low-carbon (LC) The substituted low-carbon alkyl of alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-N (H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16、R17And R19It is H and R18Be-F ,-Cl, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22, or-N (R22)2.At some embodiments In, R16、R17And R19It is H and R18It is-F ,-Cl or-O-R20.R in some embodiments16、R17And R19It is H and R18Be- F ,-Cl or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R16、R18And R19It is H and R17It is-F ,-Cl ,-Br, low-carbon (LC) The substituted low-carbon alkyl of alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-N (H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16、R18And R19It is H and R17Be-F ,-Cl, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22Or-N (R22)2.At some embodiments In, R16、R18And R19It is H and R17It is-Cl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino or-O-R20.Some embodiment party In formula, R16、R18And R19It is H and R17It is-Cl ,-CF3、O-CH3Or morpholine-4-base.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R17、R18And R19It is H and R16It is-F ,-Cl ,-Br, low-carbon (LC) The substituted low-carbon alkyl of alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S(O)2-R21、-N (H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R17、R18And R19It is H and R16Be-F ,-Cl, The substituted low-carbon alkyl of low-carbon alkyl, fluorine, cycloalkyl amino ,-O-R20、-N(H)-R22Or-N (R22)2.At some embodiments In, R17、R18And R19It is H and R16It is-F ,-CF3, morpholine-4-base ,-O-CH3、-O-CH2CH3、-O-CH(CH3)2、-O- CH2CF3,-O-ring amyl group ,-O-ring hexyl or-N (H)-CH3.In some embodiments, R17、R18And R19It is H and R16Be- F、-CF3Or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R16And R17It is H；And R18And R19Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16And R17It is H；And R18With R19It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R16And R17It is H；And R18And R19It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R16And R18It is H；And R17And R19Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16And R18It is H；And R17With R19It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R16And R18It is H；And R17And R19It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R16And R18It is H；And R17And R19It is-CF independently3Or-O-CH3.Other variablees all As defined herein.
In some embodiments of the compound of Formula II a, R16And R19It is H；And R17And R18Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R16And R19It is H；And R17With R18It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R16And R19It is H；And R17And R18It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R16And R19It is H；And R17And R18It is-F or-O-CH independently3.Other variablees all are such as Define herein.
In some embodiments of the compound of Formula II a, R17And R18It is H；And R16And R19Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22,-N (R22)2Or-N (H)-S (O)2-R23.In some embodiments, R17And R18It is H；And R16With R19It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R17And R18It is H；And R16And R19It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.Other variablees all are as defined herein.
In some embodiments of the compound of Formula II a, R17And R19It is H；And R16And R18Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R17And R19It is H；And R16With R18It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R17And R19It is H；And R16And R18It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R17And R19It is H；And R16And R18It is-F ,-Cl or-O-CH independently3.All other becomes Amount is as defined herein.
In some embodiments of the compound of Formula II a, R18And R19It is H；And R16And R17Be independently-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R20、-S (O)2-R21、-N(H)-R22、-N(R22)2Or-N (H)-S (O)2-R23.In some embodiments, R18And R19It is H；And R16With R17It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently20、-N(H)-R22Or-N (R22)2.In some embodiments, R18And R19It is H；And R16And R17It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R18And R19It is H；And R16And R17It is-CF independently3、-O-CH3Or-N (CH3)2.All Other variable is as defined herein.
In an embodiment of Formula II and the compound of II ' and IIa, compound is selected from: [6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-2027), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-base Methyl)-amine (P-2029), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2031), (5-chloro-pyridine-2-ylmethyl)-[the fluoro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2047), (5-fluoro-6-methoxv-pyridine-3-base Methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2048), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2049), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2050), (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-2051), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2052), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-[(S)-1-(4-fluoro-phenyl)-ethyl]-amine (P-2058), [6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 2062), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxyl group-pyrrole Pyridine-4-ylmethyl)-amine (P-2065), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(2-methvl-pyridinium-4-ylmethyl)-amine (P-2067), (5-fluoro-2-methoxv-pyridine-4-ylmethyl)-[6-is fluoro- 5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2071), (2,5-dimethoxys- Benzyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2086), (3,5-Dimethoxy-benzyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2087), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-2088), (3-bromo-pyridin-4-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2089), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(2-morpholine-4-base-pyridin-3-yl methyl)-amine (P-2090), [6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-morpholine-4-base-pyridin-3-yl methyl)-amine (P-2091), (3-chloro-pyridin-4-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2092), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(5-fluoro-pyridine-2-ylmethyl)-amine (P-2093), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(3-fluoro-pyridin-4-yl methyl)-amine (P-2094), (5-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl-pyrimidine-2-base)-methyl-amine (P-2095), [6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-[2-(2,2,2-tri-fluoro-ethoxies Base)-pyridin-3-yl methyl]-amine (P-2096), (2,6-dimethoxy-pyridin-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2097), (5-fluoro-2-Methanesulfonyl-benzYl)- [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2098), (the chloro-pyrrole of 5- Pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2099), (5-bromo-pyridine-2-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-amine (P-2100), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(3-methvl-pyridinium-4-ylmethyl)-amine (P-2101), (the fluoro-benzyl of the chloro-5-of 3-)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2102), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-fluoro-pyridin-3-yl methyl)-amine (P-2103), (3,5-dimethyl-benzyl Base)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2104), [6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-methoxv-pyridine-3-Ji Jia Base)-amine (P-2105), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2- Methyl-pvrimidine-5-ylmethyl)-amine (P-2106), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-methylamino-pyridin-3-yl methyl)-amine (P-2107), (3,5-double-romethyl-benzy)-[6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2108), [6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-methoxv-pyridine-3-ylmethyl)-amine (P- 2109), (2-ethyoxyl-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2110), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(2-isopropoxy-pyridin-3-yl methyl)-amine (P-2111), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(4-methvl-pyridinium-2-ylmethyl)-amine (P-2112), (2-cyclopentyloxy-pyrrole Pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2113), (2-cyclohexyloxy-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2114), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(2-trifluoromethylpyridin-3-ylmethyl)-amine (P-2115), (the chloro-5-of 2-fluoro-pyridin-4-yl methyl)-[6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2116), 4-{ [the fluoro-5-of 6- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-pyridine-2-nitrile (P- 2117), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-fluoro-pyridine-4- Ylmethyl)-amine (P-2118), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (2-trifluoromethylpyridin-4-ylmethyl)-amine (P-2119), (2-chloro-pyridin-4-yl methyl)-[the fluoro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2120), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-morpholine-4-base-pyridin-4-yl methyl)-amine (P-2121), [6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-pyrrolidin-1-yl-pyridine-4- Ylmethyl)-amine (P-2122), (the chloro-2-of 5-fluoro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methvl-pyridinium-2-base]-amine (P-2123), (4-chloro-2-Methanesulfonyl-benzYl)-[the fluoro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2124), (2-Dimethylamino-benzyl)-[6-is fluoro- 5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2125), (2-ethyl-pyrimidin- 5-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2126), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-propyl-pyrimidin- 5-ylmethyl)-amine (P-2127), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(2-isopropyl-pyrimidine-5-ylmethyl)-amine (P-2128), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-[2-(2-methox-etlayl)-pyrimidine-5-ylmethyl]-amine (P-2129), (2-butyl-phonetic Pyridine-5-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2130), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-methvl-pyridinium- 2-ylmethyl)-amine (P-2131), (3-fluoro-5-Methyl-benzvl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-2132), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(3-methoxyl group-5-romethyl-benzy)-amine (P-2133), (3-fluoro-5-methyoxy-benzyl)-[6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2134), [6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(3,4,5-trimethoxy-benzyl)-amine (P- 2150), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-pyrrolidine-1- Base-pyridine-2-ylmethyl)-amine (P-2151), the fluoro-3-{ of 5-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base amino]-methyl-1-methyl isophthalic acid H-pyridin-2-ones (P-2156), [5-(5-chloro-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P- 2165), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxyl group-6- Trifluoromethylpyridin-3-ylmethyl)-amine (P-2166), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(2-dimethylamino-6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2167), [6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxyl group-4-trifluoromethylpyridin-3-base Methyl)-amine (P-2186), ethyl sulfonic acid (2-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base amino]-methyl-phenyl)-amide (P-2198), ethyl sulfonic acid (the fluoro-3-{ of 4-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl-phenyl)-amide (P-2199), (3-is fluoro-for ethyl sulfonic acid 5-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-phenyl)- Amide (P-2202), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group- 3-pyridine radicals) methyl] pyridine-2-amine (P-2203), 3-[[the fluoro-6-of 2-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methylamino]- 3-pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2204), the chloro-N-of 6-[(5-fluoro-2-methoxyl group-3-pyrrole Piperidinyl) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] pyridine-2-amine (P-2205), 6-be fluoro- N-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-3-yl] Methyl] pyridine-2-amine (P-2206), and its any salt, prodrug, tautomer or stereoisomer.
In a third aspect, the invention provides there is formula III ' compound:
Or its salt, prodrug, tautomer or stereoisomer,
Wherein:
R24、R25、R26And R27Each is substituted low independently selected from-H, halogen, low-carbon alkyl, low-carbon alkoxy, halogen The substituted low-carbon alkyl of carbon alkyl, low-carbon alkoxy, alkoxyl, cycloalkyl amino ,-CN ,-O-R28、-S(O)2-R29、-S(O)2- N(H)-R30、-N(H)-R30、-N(R30)2With-N (H)-S (O)2-R31, condition is R24、R25、R26And R27In at least two be- H；R28It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；R29It it is low-carbon alkyl； R30It it is low-carbon alkyl；And R31It it is low-carbon alkyl.
At formula III ' compound some embodiments in, R6Take selected from halogen, low-carbon alkyl, low-carbon alkoxy, fluorine The low-carbon alkyl in generation, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N(H)- R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, wherein pyrrole Oxazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl.At formula III ' compound other embodiment in, R6Be F, Cl, The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, low carbon chain thiazolinyl ,-CN ,-C (O)-N (H)-R14、-N(H)-C(O)-R15、-C (O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14Or-N (H)-S (O)2-R15.In some embodiments, R6Be methyl, Ethyl, propyl group, butyl, amyl group or hexyl.Other variablees all are as defined herein.
In some embodiments, it is provided that there is the compound of the structure according to formula II below I:
Or its salt, prodrug, tautomer or stereoisomer,
Wherein:
R24、R25、R26And R27Independently selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, methoxyl group Substituted low-carbon alkyl, cycloalkyl amino ,-CN ,-O-R28、-S(O)2-R29、-S(O)2-N(H)-R30、-N(H)-R30、-N (R30)2With-N (H)-S (O)2-R31, condition is R24、R25、R26And R27In at least two be-H；
R28It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；
R29It it is low-carbon alkyl；
R30It it is low-carbon alkyl；And
R31It it is low-carbon alkyl.
In some embodiments of the compound of formula III and III ', R24、R25、R26And R27Each independently selected from- The substituted low-carbon alkyl of H ,-F ,-Cl ,-Br, low-carbon alkyl, fluorine, low-carbon alkoxy, the low-carbon alkyl of methoxy substitution, cycloalkyl Amino ,-CN ,-O-R20、-S(O)2-R21、-S(O)2-N(H)-R22、-N(H)-R22、-N(R22)2With-N (H)-S (O)2-R23, bar Part is R24、R25、R26And R27In at least two be-H.In some embodiments, R24、R25、R26And R27Each is independently Selected from H, halogen, low-carbon alkyl, low-carbon alkoxy, the substituted low-carbon alkyl of halogen ,-OR20, or the substituted lower alkanes of alkoxyl Base.Other variablees all are as defined herein.
In some embodiments of the compound of formula III and III ', R24、R25And R26It is H and R27Be-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R28、-S (O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R24、R25And R26Be H and R27It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R28、-N(H)-R30Or-N (R30)2.One In a little embodiments, R24、R25And R26It is H and R27It is the substituted low-carbon alkyl of fluorine or-O-R28.In some embodiments, R24、R25And R26It is H and R27It is-CF3Or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of formula III and III ', R24、R25And R27It is H and R26Be-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R28、-S (O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R24、R25And R27Be H and R26It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R28、-N(H)-R30Or-N (R30)2.One In a little embodiments, R24、R25And R27It is H and R26It is-F ,-Cl or-O-R28.In some embodiments, R24、R25And R27 It is H and R26It is-F ,-Cl or-O-CH3.Other variablees all are as defined herein.
In some embodiments of the compound of formula III and III ', R24、R26And R27It is H and R25Be-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R28、-S (O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R24、R26And R27Be H and R25It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R28、-N(H)-R30Or-N (R30)2.One In a little embodiments, R24、R26And R27It is H and R25It is-Cl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino or-O-R28.? In some embodiments, R24、R26And R27It is H and R25It is-Cl ,-CF3、-O-CH3Or 4-thyl-piperazin-1-base.All its Its variable is as defined herein.
In some embodiments of the compound of formula III and III ', R25、R26And R27It is H and R24Be-F ,-Cl ,- The substituted low-carbon alkyl of Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O-R28、-S (O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R25、R26And R27Be H and R24It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R28、-N(H)-R30Or-N (R30)2.One In a little embodiments, R25、R26And R27It is H and R24It is-F ,-CF3, morpholine-4-base ,-O-CH3、-O-CH2CH3、-O-CH (CH3)2、-O-CH2CF3,-O-ring amyl group ,-O-ring hexyl or-N (H)-CH3.In some embodiments, R25、R26And R27It is H And R24It is-F ,-CF3、-O-CH3、-O-CH2CH3Or-O-ring amyl group.Other variablees all are as defined herein.
In some embodiments of the compound of formula III and III ', R24And R25It is H；And R26And R27Be independently- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R28、-S(O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R24And R25It is H；And And R26And R27It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently28、-N(H)-R29 Or-N (R30)2.In some embodiments, R24And R25It is H；And R26And R27It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.Other variablees all are as defined herein.
In some embodiments of the compound of formula III and III ', R24And R26It is H；And R25And R27Be independently- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R28、-S(O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R24And R26It is H；And And R25And R27It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently28、-N(H)-R30 Or-N (R30)2.In some embodiments, R24And R26It is H；And R25And R27It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R24And R26It is H；And R25And R27It is-CF independently3Or-O-CH3.Other variablees all As defined herein.
In some embodiments of the compound of formula III and III ', R24And R27It is H；And R25And R26Be independently- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R28、-S(O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R24And R27It is H；And And R25And R26It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently28、-N(H)-R30 Or-N (R30)2.In some embodiments, R24And R27It is H；And R25And R26It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R24And R27It is H；And R25And R26It is-F or-O-CH independently3.Other variablees all are such as As defined herein.
In some embodiments of the compound of formula III and III ', R25And R26It is H；And R24And R27Be independently- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R28、-S(O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R25And R26It is H；And And R24And R27It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently28、-N(H)-R30 Or-N (R30)2.In some embodiments, R25And R26It is H；And R24And R27It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.Other variablees all are as defined herein.
In some embodiments of the compound of formula III and III ', R25And R27It is H；And R24And R26Be independently- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R28、-S(O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R25And R27It is H；And And R24And R26It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently28、-N(H)-R30 Or-N (R30)2.In some embodiments, R25And R27It is H；And R24And R26It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R25And R27It is H；And R24And R26It is-F or-O-CH independently3.Other variablees all are such as As defined herein.
In some embodiments of the compound of formula III and III ', R26And R27It is H；And R24And R25Be independently- The substituted low-carbon alkyl of F ,-Cl ,-Br, low-carbon alkyl, fluorine, the low-carbon alkyl of methoxy substitution, cycloalkyl amino ,-CN ,-O- R28、-S(O)2-R29、-N(H)-R30、-N(R30)2Or-N (H)-S (O)2-R31.In some embodiments, R26And R27It is H；And And R24And R25It is-F ,-Cl, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, cycloalkyl amino ,-O-R independently28、-N(H)-R30 Or-N (R30)2.In some embodiments, R26And R27It is H；And R24And R25It is-F ,-Cl, CF independently3、-O-CH3Or-N (CH3)2.In some embodiments, R26And R27It is H；And R24And R25It is-CF independently3、-O-CH3Or-N (CH3)2.All Other variable is as defined herein.
In an embodiment of formula III and the compound of III ', compound is selected from:
(5-fluoro-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-amine (P-1569), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoro Methvl-pyridinium-3-ylmethyl)-amine (P-1570), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2057), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2061), (2-methoxv-pyridine- 4-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2069), (5- Fluoro-2-methoxv-pyridine-4-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-2072), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyrimidine-2-base]-amine (P-2073), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-phonetic Pyridine-2-base]-pyridine-2-ylmethyl-amine (P-2076), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyrimidine-2-base]-pyridin-3-yl methyl-amine (P-2077), (6-chloro-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2078), (6-methvl-pyridinium-2-ylmethyl)-[5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2079), [5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2080), [5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-morpholine-4-base-pyridine-2-ylmethyl)-amine (P-2081), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-pyrrolidin-1-yl- Pyridine-2-ylmethyl)-amine (P-2082), (5-EthylPyridine-2-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2083), (3-methvl-pyridinium-4-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2084), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyrimidine-2-base]-(2-morpholine-4-base-pyridin-4-yl methyl)-amine (P-2085), [5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-pyridin-4-yl methyl-amine (P-2138), (2-methoxyl group-pyrrole Pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2139), [6-(4-thyl-piperazin-1-base)-pyridin-3-yl methyl]-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-amine (P-2140), (2-methvl-pyridinium-4-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2141), (2-ethyoxyl-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2142), (2-cyclopentyloxy-pyridin-3-yl methyl)- [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2148), (2-cyclopentyloxy- Pyridin-4-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P- , and its any salt, prodrug, tautomer or stereoisomer 2149).
In fourth aspect, it is provided that compound, wherein compound is selected from:
[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2,6-dimethoxys-pyrrole Pyridine-3-ylmethyl)-amine (P-1496), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-1507), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1511), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1512), (5-fluoro-pyridin-3-yl methyl)-[5- (1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1514), (6-methoxv-pyridine-3-Ji Jia Base)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1517), [5-(1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1518), (2-methoxy Base-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1519), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(5-fluoro-pyridin-3-yl methyl)-amine (P- 1522), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-methoxv-pyridine-3-base Methyl)-amine (P-1526), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(2-methoxy Base-pyridin-3-yl methyl)-amine (P-1527), (5-fluoro-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1530), (6-methoxv-pyridine-3-ylmethyl)-[6-methyl-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1532), (5-fluoro-pyridin-3-yl methyl)- [6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1534), [6-first Base-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-base Methyl)-amine (P-1538), (2-methoxv-pyridine-3-ylmethyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1539), [the chloro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1541), [the chloro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1545), [the chloro-5-of 6- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1546), (5-fluoro-pyridin-3-yl methyl)-[3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-1549), [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1552), [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1553), (6-methoxy Base-pyridin-3-yl methyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-1554), (5-fluoro-pyridin-3-yl methyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1556), [3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1560), (2-methoxv-pyridine-3-Ji Jia Base)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1561), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-base Methyl)-amine (P-1562), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-1564), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1568), (5-fluoro-pyridin-3-yl methyl)-[5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1580), [5-(5-methoxyl group-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1583), (5-fluoro-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-1585), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-1589), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1591), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1595), [6-chloro-5-(5-methoxy Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 1596), (5-fluoro-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-amine (P-1601), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyrimidine-2-base]-amine (P-1604), [5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyrimidine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1605), (2-methoxv-pyridine-3-ylmethyl)-[5- (5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1606), [5-(5-chloro-1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 1609), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(2-methoxv-pyridine-3-base Methyl)-amine (P-1614), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6- Methoxv-pyridine-3-ylmethyl)-amine (P-1622), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1624), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1628), [6-fluoro-5-(5- Fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 1629), (5-fluoro-pyridin-3-yl methyl)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-1631), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-methoxyl group- Pyridin-3-yl methyl)-amine (P-1635), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]- (6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1636), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1637), (5-fluoro-pyridin-3-yl methyl)-[5- (5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1639), (6-methoxyl group-pyrrole Pyridine-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 1643), (6-trifluoromethylpyridin-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-1644), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1645), (5-fluoro-pyridin-3-yl methyl)-[6-fluoro-5-(5- Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1647), [6-fluoro-5-(5-trifluoro Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P- 1651), [the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-fluoroform Base-pyridin-3-yl methyl)-amine (P-1652), [the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1653), the fluoro-6-of 3-{2-[(6-methoxv-pyridine- 3-ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1658), the fluoro-6-of 3-{2- [(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P- 1659), the fluoro-6-of 3-{2-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3- B] pyridine-5-nitrile (P-1660), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-1662), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1666), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1667), [5-(5-cyclopropyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 1668), N-(the fluoro-6-of 3-{2-[(5-fluoro-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3- B] pyridine-5-base)-acetamide (P-1671), N-(the fluoro-6-of 3-{2-[(6-methoxv-pyridine-3-ylmethyl)-amino]-pyrrole Pyridine-3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1674), N-(3-{2-fluoro-6-[(6-trifluoro Methvl-pyridinium-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P- 1675), N-(the fluoro-6-of 3-{2-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo- [2,3-b] pyridine-5-base)-acetamide (P-1676), N-(the fluoro-6-of 3-{2-[(5-fluoro-pyridin-3-yl methyl)-amino]-pyrrole Pyridine-3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1678), N-(3-{2-fluoro-6-[(6-first Epoxide-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1682), N-(the fluoro-6-of 3-{2-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrole Cough up also [2,3-b] pyridine-5-base)-Methanesulfomide (P-1683), N-(the fluoro-6-of 3-{2-[(2-methoxv-pyridine-3-Ji Jia Base)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1684), [the fluoro-5-of 6- (5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1686), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-first Epoxide-pyridin-3-yl methyl)-amine (P-1690), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1691), [the fluoro-5-of 6-(5-mesyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 1692), the fluoro-6-of 3-{2-[(5-fluoro-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyrrole Pyridine-5-acid methylamide (P-1695), the fluoro-6-of 3-{2-[(6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl first Base }-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1699), the fluoro-6-of 3-{2-[(6-trifluoromethylpyridin-3- Ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1700), 3-{2- Fluoro-6-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-carboxylic Acid Methanamide (P-1701), 4-[4-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridine-3- Ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-pyrazol-1-yl]-piperidines-1-carboxylic acid tert-butyl ester (P-1702), { 6- Fluoro-5-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }- (5-fluoro-pyridin-3-yl methyl)-amine (P-1705), { the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrroles And [2,3-b] pyridin-3-yl methyl]-pyridine-2-base-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1708), { 6-is fluoro- 5-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-(6- Trifluoromethylpyridin-3-ylmethyl)-amine (P-1709), { the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1710), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)- Amine (P-1712), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxyl group- Pyridin-3-yl methyl)-amine (P-1716), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1717), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1718), 3-{6-[(5-fluoro-pyridine-3- Ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1719), 3-{6-[(6-methoxy Base-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1723), 3- { 6-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1724), 3-{6-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] Pyridine-4-nitrile (P-1725), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-1727), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(4-methyl-7H-pyrroles And [2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-amine (P-1728), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)- [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-amine (P-1729), [the fluoro-5-of 6- (4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)- Amine (P-1730), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-(6-methoxy Base-pyridin-3-yl methyl)-amine (P-1731), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)- Pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1732), (5-fluoro-6-methoxv-pyridine-3-Ji Jia Base)-[the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-amine (P-1733), [6- Fluoro-5-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-(2-methoxv-pyridine-3-Ji Jia Base)-amine (P-1734), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-is fluoro- Pyridin-3-yl methyl)-amine (P-2001), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]- [(S)-1-(4-fluoro-phenyl)-ethyl]-amine (P-2005), (the chloro-benzyl of 3-)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-1-methyl isophthalic acid H-pyrazole-3-yl]-amine (P-2006), (3-chloro-4-Methyl-benzvl)-[5-(chloro-1H-of 5- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2007), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyrimidine-2-base]-(3,4-diiluoro-benzyl)-amine (P-2008), [5-(5-chloro-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-(3-fluoro-5-romethyl-benzy)-amine (P-2009), [5-(the chloro-1H-pyrroles of 5- And [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-trifluoromethoxy-benzyl)-amine (P-2010), [(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-fluoro-4-romethyl-benzy)-amine (P-2011), (the chloro-benzyl of 4-)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-methyl-amine (P- 2012), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-Methyl-benzvl)-amine (P- 2013), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-fluoro-4-Methyl-benzvl)- Amine (P-2014), [2-(the chloro-phenyl of 3-)-ethyl]-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-amine (P-2015), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1H-pyrazole-3-yl]-(4-is fluoro- Benzyl)-amine (P-2016), [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxy Base-pyridin-3-yl methyl)-amine (P-2017), [5-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2018), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2019), [2-(the chloro-phenyl of 2-)- Ethyl]-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2020), [(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-[2-(4-fluoro-phenyl)-ethyl]-amine (P-2021), [5- (5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-[2-(6-methvl-pyridinium-2-base)-ethyl]- Amine (P-2022), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethyl-pyrrole Pyridine-3-ylmethyl)-amine (P-2023), [5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2024), butyl-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyrimidine-2-base]-amine (P-2026), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-2028), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2030), (the chloro-benzyl of 4- Base)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2032), (the fluoro-benzyl of 2-)-[5-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2033), (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2034), (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2035), (the chloro-benzyl of 2-)-[5-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2036), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-2037), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2038), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-(1-thiazol-2-yl-ethyl)-amine (P-2039), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2043), (the chloro-pyridine of 5-- 2-ylmethyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2044), [6- Fluoro-5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2045), [1-(4-fluoro-phenyl)-propyl group]-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-2053), [1-(4-fluoro-phenyl)-cyclopropyl]-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-amine (P-2055), [(S)-1-(4-fluoro-phenyl)-ethyl]-[5-(5-fluoro-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2056), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyrimidine-2-base]-(2-methoxv-pyridine-4-ylmethyl)-amine (P-2074), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-6-fluoro-pyridine-2-base]-(2-methvl-pyridinium-4-ylmethyl)-amine (P-2075), (5-fluoro-2-methoxyl group-pyrrole Pyridine-4-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2135), (5-is fluoro- 2-methoxv-pyridine-4-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-2136), [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2143), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-thiazol-2-yl]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2144), [5-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2145), [the fluoro-5-of 3- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)- Amine (P-2146), [the fluoro-5-of 3-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-tri- Methyl fluoride-pyridin-3-yl methyl)-amine (P-2147), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiophene Azoles-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2154), (6-methoxv-pyridine-3-ylmethyl)-[5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-2155), 3-{ [5-(the chloro-1H-pyrroles of 5- And [2,3-b] pyridin-3-yl methyl)-pyrimidine-2--amino]-methyl-5-fluoro-1-methyl isophthalic acid H-pyridin-2-ones (P- 2157), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(2-methoxv-pyridine-3-base Methyl)-amine (P-2158), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-thiazol-2-yl]-amine (P-2159), (6-methoxv-pyridine-2-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-2162), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-thiazol-2-yl]-(6-methoxv-pyridine-2-ylmethyl)-amine (P-2163), [5-(5-chloro-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (P-2164), the fluoro-N-of 5- [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-2-methoxy-nicotinamide (P- 2168), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-3-fluoro-pyridine-2-base]-(6-trifluoromethyl-pyrrole Pyridine-3-ylmethyl)-amine (P-2172), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-2176), N-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-C-phenyl-methane-sulfonamide (P-2181), and its any salt, prodrug, tautomer or vertical Body isomer.
When mentioning compound herein, pointing out on the contrary unless clear and definite, the explanation to compound or compound group includes this The salt (including pharmaceutically acceptable salt) of compound (one or more), the preparation (bag of this compound (one or more) Include pharmaceutically acceptable preparation), its conjugates, its derivant, its form, its prodrug and its all stereoisomers. When mentioning the compositions of compound as herein described (i.e. the compound of the present invention), test kit, using method etc., it should be understood that (unless otherwise noted) compound described herein include the compound of Formulas I and I ' include its all sub-embodiments, Formula II, The compound of II ' and IIa includes that the compound of its all sub-embodiments, formula III and III ' includes its all Asias The compound listed in embodiment and above fourth aspect.
In the 5th aspect, it is provided that for the treatment any Fms and/or Kit in animal target in need and/or Disease that Flt-3 is protein kinase mediated or the method for disease, wherein the method relate to giving object effective dose any one or Multiple compound as herein described.In some embodiments, the method relates to as herein describedization giving object effective dose Compound also combines one or more other therapies of this disease or disease.
In the 6th aspect, present invention provide for treatment Fms protein kinase in animal target in need and be situated between The disease led or the method for disease, wherein the method relates to any one or more as herein describedization giving object effective dose Compound.In one embodiment, the method relates to giving object effective dose compound as herein described also combines this disease Or one or more other therapies of disease.
In the 7th aspect, the present invention is provided to treat the Kit in the animal target needed protein kinase mediated Disease or the method for disease, wherein the method relates to any one or more chemical combination as herein described giving object effective dose Thing.In one embodiment, the method relates to giving object effective dose compound as herein described and combine this disease or One or more other therapies of disease.
In eighth aspect, compound as herein described will have as measured in generally acknowledged Fms Kinase activity assays Less than 500nm, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50.Real at some Executing in mode, compound is selective relative to other protein kinase, so that another the kinase whose IC considerably assessed50Divided by The kinase whose IC of Fms50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase includes but not limited to CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.
In the 9th aspect, compound as herein described will have as measured in generally acknowledged Kit Kinase activity assays Less than 500nm, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50.Real at some Executing in mode, this compounds is selective relative to other protein kinase, so that another the kinase whose IC considerably assessed50 Divided by the kinase whose IC of Kit50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase includes but not limited to CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.
In the tenth aspect, compound as herein described is dual Fms/Kit inhibitor, i.e. about suppression Fms kinases and Kit kinases, will be Approximate Equivalent.In some embodiments, this compounds will have such as generally acknowledged Fms kinase activity examination Test middle measured less than 500nm, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than 1nM's IC50And by have as suitable generally acknowledged Kit Kinase activity assays is measured less than 500nm, less than 100nM, be less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50, the wherein kinase whose IC of Kit50Kinase whose divided by Fms IC50Ratio 20 to 0.05, also have 10 to 0.1, also have in the range of 5 to 0.2.In some embodiments, compound is relative In being selective except the protein kinase of Kit, so that another the kinase whose IC considerably assessed50Divided by the kinase whose IC of Fms50 Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other egg White kinases includes but not limited to CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.In one embodiment, dual Fms/Kit inhibitor is selected from following compound:
(6-methoxv-pyridine-3-ylmethyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-1554), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1562), (6-chloro-pyridin-3-yl methyl)-[(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2003), [5-(5-chloro-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(6-fluoro-pyridin-3-yl methyl)-amine (P-2004), [5-(the chloro-1H-pyrroles of 5- And [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3,4-diiluoro-benzyl)-amine (P-2008), [5-(5-chloro-1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-Methyl-benzvl)-amine (P-2013), [5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2019), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3- Ylmethyl)-amine (P-2031), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2032), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-2037), (6-methvl-pyridinium-2-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2079), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyrimidine-2-base]-(6-morpholine-4-base-pyridine-2-ylmethyl)-amine (P-2081), [5-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-pyrrolidin-1-yl-pyridine-2-ylmethyl)-amine (P- 2082), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-methvl-pyridinium- 2-ylmethyl)-amine (P-2131), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2146), [the fluoro-5-of 3-(5-methoxyl group-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2147), (2-cyclopentyloxy- Pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P- 2148), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-methoxv-pyridine-3-base Methyl)-amine (P-2154), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-methoxy Base-pyridine-2-ylmethyl)-amine (P-2163), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) the fluoro-pyrrole of-3- Pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2172), ethyl sulfonic acid (2-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl-phenyl)-amide (P-2198), ethyl sulfonic acid (3- Fluoro-5-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-benzene Base)-amide (P-2202), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] the fluoro-N-of-6-[(5-fluoro-6-first Epoxide-3-pyridine radicals) methyl] pyridine-2-amine (P-2203), 3-[[the fluoro-6-of 2-[(5-fluoro-6-methoxyl group-3-pyridine radicals) first ammonia Base]-3-pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2204), the chloro-N-of 6-[(5-fluoro-2-methoxyl group- 3-pyridine radicals) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] pyridine-2-amine (P-2205), 6- Fluoro-N-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridine-3- Base] methyl] pyridine-2-amine (P-2206), and its any salt, prodrug, tautomer or stereoisomer.
In the 11st aspect, compound as herein described is Fms selective depressant, i.e. will choosing relative to Kit kinases Suppress to selecting property Fms kinases.In some embodiments, compound will have as measured in generally acknowledged Fms Kinase activity assays Less than 500nm, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50And work as In suitable generally acknowledged Kit Kinase activity assays, during mensuration, will have ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, go back The kinase whose IC of Kit of ＞ 70, also ＞ 80, also ＞ 90, also ＞ 10050Divided by the kinase whose IC of Fms50Ratio.At some embodiments In, compound is selective relative to the protein kinase except Kit equally, so that another the kinase whose IC considerably assessed50 Divided by the kinase whose IC of Fms50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase includes but not limited to Flt-3, CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR. In one embodiment, Fms selective depressant is selected from following compound:
[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2,6-dimethoxys-pyrrole Pyridine-3-ylmethyl)-amine (P-1496), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1622), N-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3- Ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1669), N-(3- { 6-[(6-chloro-pyridin-3-yl methyl)-amino]-2-fluoro-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5- Base)-Methanesulfomide (P-1679), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-2001), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-2028), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2029), [6-fluoro-5-(5-first Oxy-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P- 2030), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-methoxv-pyridine-3-base Methyl)-amine (P-2038), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (2-methoxv-pyridine-3-ylmethyl)-amine (P-2043), [the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2045), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)- [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2048), (the fluoro-2-of 5- Methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2049), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2- Methoxv-pyridine-3-ylmethyl)-amine (P-2052), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2057), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)- [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2061), [6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 2062), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3- Ylmethyl)-amine (P-2063), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(5-is fluoro- 2-methoxv-pyridine-3-ylmethyl)-amine (P-2064), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(2-methvl-pyridinium-4-ylmethyl)-amine (P-2067), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-2070), (5-fluoro-2-first Epoxide-pyridin-4-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2071), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyrimidine-2-base]-amine (P-2073), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-is fluoro- Pyridine-2-base]-(2-methvl-pyridinium-4-ylmethyl)-amine (P-2075), (6-chloro-pyridin-3-yl methyl)-[5-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2078), (6-chloro-pyridin-3-yl methyl)-[6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2088), (2,6-dimethoxies Base-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-2097), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(fluoro-pyrrole of 2- Pyridine-3-ylmethyl)-amine (P-2103), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(2-fluoro-pyridin-4-yl methyl)-amine (P-2118), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2139), 3-{ [5-(5-chloro-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2--amino]-methyl }-5-fluoro-1-methyl isophthalic acid H-pyridin-2-ones (P-2157), [5-(5- Chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-Ji Jia Base)-amine (P-2165), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(the fluoro-pyridine of 5-- 3-ylmethyl)-amine (P-2176), the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl Methyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2193), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) first Base] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl] pyridine-2-amine (P-2203), [[[(5-is fluoro-for the fluoro-6-of 2-for 3- 6-methoxyl group-3-pyridine radicals) methylamino]-3-pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2204), 6- Chloro-N-[(5-fluoro-2-methoxyl group-3-pyridine radicals) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl) first Base] pyridine-2-amine (P-2205), the fluoro-N-of 6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5-(trifluoromethyl)- 1H-pyrrolo-[2,3-b] pyridin-3-yl] methyl] pyridine-2-amine (P-2206), and its any salt, prodrug, make a variation mutually Structure body or stereoisomer.
In the 12nd aspect, compound as herein described is dual Fms/Flt-3 inhibitor, i.e. swashs about suppression Fms Enzyme and Flt-3 kinases, will be Approximate Equivalent.In some embodiments, compound will have such as generally acknowledged Fms kinase activity Test measures less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than 1nM IC50And by have as in suitable generally acknowledged Flt-3 Kinase activity assays measure less than 500nM, less than 100nM, be less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50, the wherein kinase whose IC of Flt-350Kinase whose divided by Fms IC50Ratio 20 to 0.05, also have 10 to 0.1, also have in the range of 5 to 0.2.In some embodiments, compound is relative In being selective except the protein kinase of Flt-3, so that another the kinase whose IC considerably assessed50Kinase whose divided by Fms IC50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other Protein kinase includes but not limited to CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.In some embodiments, should Dual Fms/Flt-3 inhibitor suppresses Kit equally.In one embodiment, this dual Fms/Flt-3 inhibitor is to be selected from down The compound of row:
(6-trifluoromethylpyridin-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-1644), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-trifluoromethyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1646), [5-(5-cyclopropyl-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1667), (6-is chloro- Pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2003), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-fluoro-pyridin-3-yl methyl)-amine (P- 2004), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-fluoro-5-trifluoromethyl-benzyl Base)-amine (P-2009), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-fluoroform Base-pyridin-3-yl methyl)-amine (P-2019), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2029), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2030), [6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2031), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2032), (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2034), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-2037), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2038), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[6-is fluoro- 5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2040), (5-fluoro-6-methoxy Base-pyridin-3-yl methyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2041), (5-chloro-pyridine-2-ylmethyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2044), (5-chloro-pyridine-2-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-2047), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2048), (the chloro-benzyl of 4-)-[6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2050), (6-methoxv-pyridine-3-Ji Jia Base)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2057), [(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)- Amine (P-2165), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group-3- Pyridine radicals) methyl] pyridine-2-amine (P-2203), 3-[[the fluoro-6-of 2-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methylamino]-3- Pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2204), the chloro-N-of 6-[(5-fluoro-2-methoxyl group-3-pyridine Base) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] pyridine-2-amine (P-2205), the fluoro-N-of 6- [(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-3-yl] first Base] pyridine-2-amine (P-2206) and its any salt, prodrug, tautomer or stereoisomer.
In one embodiment, dual Fms/Flt-3 inhibitor is selected from following compound:
(6-trifluoromethylpyridin-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-1644), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-trifluoromethyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1646), [5-(5-cyclopropyl-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1667), [5-(5- Chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3-fluoro-5-romethyl-benzy)-amine (P- 2009), (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2034), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2037), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2040), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)- [the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2041), (5-chloro-pyridine-2-base Methyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2044), (the chloro-pyrrole of 5- Pyridine-2-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2047), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-2050), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group-3- Pyridine radicals) methyl] pyridine-2-amine (P-2203), 3-[[the fluoro-6-of 2-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methylamino]-3- Pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2204), the chloro-N-of 6-[(5-fluoro-2-methoxyl group-3-pyridine Base) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] pyridine-2-amine (P-2205), the fluoro-N-of 6- [(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-3-yl] first Base] pyridine-2-amine (P-2206) and its any salt, prodrug, tautomer or stereoisomer.
Additionally for any aspect that present document relates to and embodiment, compound as herein described suppresses kinase mutant equally The effect of (such as Fms mutant, Kit mutant, Flt-3 mutant), described kinase mutant includes but not limited to and disease shape The sudden change that state such as cancer is relevant.
In the 13rd aspect, it is provided that compositions, it any one or more institute herein including treating effective dose The compound stated and at least one pharmaceutically acceptable carrier, excipient and/or diluent, it includes any two or more The combination of compound as herein described.Said composition can farther include the compound of multiple different pharmacologically active, and it can include Multiple compound as herein described.In some embodiments, said composition can include that any one or more is as herein described Compound is together with one or more compounds effectives upper for the treatment of same disease indication.On the one hand, said composition bag Include any one or more compound as herein described upper effective for the treatment of same disease indication together with one or more Compound, wherein this compound has cooperative effect for this disease indication.In one embodiment, said composition includes In treatment cancer, effective any one or more compound as herein described is being treated in identical cancer with one or more Other compound effective, wherein this compound is collaborative effective in treatment cancer.
In fourteenth aspect, it is provided that method, it is by by any one or more of protein kinase and effective dose originally Compound contact described in literary composition, regulation Fms and/or Kit and/or Flt-3 protein kinase include what it arbitrarily suddenlyd change Activity.
In the 15th aspect, the invention provides method, its by give object effective dose in need include appoint Anticipate the compositions of one or more compounds described herein, treatment in object by Fms and/or Kit and/or Flt-3 Disease or disease including its any sudden change mediation.In one embodiment, the invention provides method, it is by giving Give the compositions including any one or more compound described herein this disease of combined treatment of object effective dose in need One or more sick other applicable therapies, by Fms and/or Kit, treatment includes that it arbitrarily suddenlys change in object The disease of mediation or disease.
In the 16th aspect, the invention provides method, its by give object effective dose in need include appoint The compositions treatment of one or more compounds described herein of anticipating is included its Jie that arbitrarily suddenlys change by Fms in object The disease led or disease.In one embodiment, the invention provides method, it is by giving object effective dose in need The compositions including any one or more compound described herein and this disease of combined treatment one or more other fit Close therapy, the treatment disease or the disease that are included its mediation that arbitrarily suddenlys change by Fms in object.
In the 17th aspect, the invention provides method, its by give object effective dose in need include appoint Anticipate the compositions of one or more compounds described herein, by Kit, treatment includes that it arbitrarily suddenlys change in object The disease of mediation or disease.In one embodiment, the invention provides method, it is effective by giving object in need The compositions including any one or more compound described herein of amount this disease of combined treatment one or more other It is suitable for therapy, the treatment disease or the disease that are included its mediation that arbitrarily suddenlys change by Kit in object.
In the 18th aspect, the invention provides method, its by give object effective dose in need include appoint Anticipate the compositions of one or more compounds described herein, by Flt-3, treatment includes that it is the most prominent in object Become disease or the disease of mediation.In one embodiment, the invention provides method, it is in need right by giving The compositions including any one or more compound described herein the one of this disease of combined treatment or many as effective dose Planting other applicable therapy, treatment is included its disease that arbitrarily sudden change mediates or disease by Flt-3 in object.
In the 19th aspect, the invention provides method, its by give object effective dose in need include appoint Anticipate the compositions of one or more compounds described herein, by Fms and Flt-3, treatment includes that it is the most prominent in object Become disease or the disease of mediation.In one embodiment, the invention provides method, it is in need right by giving The compositions including any one or more compound described herein the one of this disease of combined treatment or many as effective dose Planting other applicable therapy, treatment is included its disease that arbitrarily sudden change mediates or disease by Fms and Flt-3 in object Disease.
In the 20th aspect, the invention provides method, its by give object effective dose in need include appoint Anticipate the compositions of one or more compounds described herein, by Fms and Kit, treatment includes that it is the most prominent in object Become disease or the disease of mediation.In one embodiment, the invention provides method, it is in need right by giving The compositions including any one or more compound described herein the one of this disease of combined treatment or many as effective dose Planting other applicable therapy, treatment is included its disease that arbitrarily sudden change mediates or disease by Fms and Kit in object.
In the 21st aspect, the invention provides treatment method of cancer in object in need, it is by giving Give including any one or the compositions of multiple compound described herein and combining one or more and controlling of object effective dose Treat in cancer effective other therapies or therapy and carry out.Other therapies or therapy include suitable anti-cancer therapies (such as surgical operation, radiation are controlled for (such as pharmacotherapy, vaccine therapy, gene therapy, photodynamic therapy) or therapy Treatment, hyperthermia (hyperthermia heating), bone marrow or stem cell transplantation).In one embodiment, a kind of or many Plant suitable anti-cancer therapies or therapy selected from using the treatment of chemotherapeutics (such as chemotherapeutics), radiotherapy (such as x- Ray, gamma-radiation or electronics, proton, neutron or alpha-particle bundle), hyperthermia (such as microwave, ultrasound wave, radio-frequency (RF) ablation), Vaccine therapy (such as AFP gene hepatocarcinoma vaccine, AFP adenovirus carrier vaccine, AG-858, allos GM-CSF-secretion mammary gland Theratope, dendritic cell peptide vaccine), gene therapy (such as Ad5CMV-p53 carrier, coding the adenovirus vector of MDA7, adenopathy Poison 5-tumor necrosis factor α), photodynamic therapy (such as amino-laevulic acid, motexafin lutecium (motexafin Lutetium)), surgical operation or bone marrow and stem cell transplantation.
In the 22nd aspect, the invention provides treatment method of cancer in object in need, it is by giving Give the compositions including any one or more of compound described herein of object effective dose and to combine one or more suitable Chemotherapeutics and carry out.In one embodiment, one or more suitable chemotherapeutics are selected from alkylating agent, and it includes but not limited to Adozelesin, altretamine, benzene reach not STING, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, benzene fourth Acid chlormethine, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine, marfanil (hepsulfam), different Cyclophosphamide, an improsulfan, irofulven, lomustine, mannomustine, chlormethine, melphalan, mitobronitol, nedaplatin, Buddhist nun Mo Siting, oxaliplatin, piposulfan, prednimustine, methylbenzyl hydrazine, Ranimustine, Satraplatin (satraplatin), Si Mosi Spit of fland, streptozocin, temozolomide, phosphinothioylidynetrisaziridine, treosulfan, triaziquone, tretamine, four nitric acid three platinum (triplatin Tetranitrate), trofosfamide and uracil mustard；Antibiotic, it includes but not limited to aklavine, pacifies soft ratio star, rich Lay mycin, dactinomycin, daunorubicin, amycin, elsamitrucin, epirubicin, darubicin, menogaril, mitomycin, Neocarzinostain NCS, pentostatin, Perarubicin and plicamycin, valrubicin and zorubicin；Antimetabolite, it includes But it is not limited to aminopterin-induced syndrome, azacitidine, imuran, capecitabine, cladribine, clofarabine, cytosine arabinoside, Di Xi His shore, floxuridine, fludarabine (fludarabine), 5-fluorouracil, gemcitabine, hydroxyurea, purinethol, first ammonia butterfly Purine, nelarabine 506u, pemetrexed, Raltitrexed, ftorafur uracil, thioguanine, trimethoprim, trimetrexate and arabinose gland Glycosides；Immunotherapy, it includes but not limited to alemtuzumab, bevacizumab, Cetuximab, galiximab, gemtuzumab Ozogamicin Mylotarg CDP 771, handkerchief Buddhist nun's monoclonal antibody, handkerchief trastuzumab (pertuzumab), Rituximab, tositumomab, trastuzumab, 90Y ibritumomab tiuxetan, easily Puli's nurse agate and tremelimumab；Hormone or hormone antagonist, it includes but not limited to Anastrozole, androgen, Bu Sherui Woods, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, indole former times sweet smell, letrozole, acetic acid bright third Rayleigh, Mai Gesi alcohol (magestrol), raloxifene, tamoxifen and toremifene；Taxane, it includes but not limited to DJ- 927, docetaxel, TPI 287, La Luotasai (larotaxel), Ao Tatasai (ortataxel), paclitaxel, DHA-Ramulus et folium taxi cuspidatae Alcohol and tesetaxel (tesetaxel)；Retinoid, it includes but not limited to alitretinoin, bexarotene, fenretinide, different Tretinoin and tretinoin；Alkaloid, includes but not limited to Demecolcine, homoharringtonine, vinblastine, vincristine, long fields for spring sowing Pungent, vinflunine and vinorelbine；Anti-angiogenic, includes but not limited to AE-941 (GW786034, Neovastat), ABT- 510,2ME2, lenalidomide and Thalidomide；Topoisomerase enzyme inhibitor, includes but not limited to amsacrine, shellfish Lip river (is also alive for health, Yi Dukaruien (edotecarin), etoposide, etoposide phosphate, exatecan, Irinotecan Property metabolite SN-38 (SN38)), lucanthone (lucanthone), mitoxantrone, a shirt fine jade (pixantrone), rubitecan, teniposide, topotecan and 9-aminocamptothecin；Inhibitors of kinases, including but do not limit In Axitinib (AG-013736), Dasatinib (BMS-354825), erlotinib, gefitinib, Flavopiridol, methanesulfonic acid Imatinib, Lapatinib, diphosphonic acid be not for husky Buddhist nun (AMG 706), AMN107 (AMN107), plug profit Seeley (seliciclib), Sorafenib, Sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxyl star spore bacterium Element) and vatalanib；Phasing signal transduction inhibitor (targeted singnal transduction inhibitor), bag Include but be not limited to bortezomib, geldanamycin and rapamycin；Biological respinse modifier, include but not limited to imiquimod, Interferon-' alpha ' and interleukin II；With other chemotherapy, include but not limited to 3-AP (3-amino-2-carboxyl al amino Thiourea), atrasentan (altrasentan), aminoglutethimide, anagrelide, asparaginase, Bryostatin-1, Xi Lunji Peptide, department of Erie not, methanesulfonic acid eribulin (E7389), ipsapirone, lonidamine, masoprocol, methyl-GAG, Ao Limosen (oblimersen), sulindac, testolactone, tiazofurine, mTOR inhibitors (such as rapamycin (temsirolimus, Temsirolimus), everolimus, 42-(dimethyl Asia phosphono) rapamycin (deforolimus)), PI3K inhibitor (example Such as BEZ235, GDC-0941, XL147, XL765), Cdk4 inhibitor (such as PD-332991), Akt inhibitor, Hsp90 suppression Agent (such as KOS-953) and farnesyl transferase inhibitor (such as pyrrole method Buddhist nun).Preferably, the method for this treatment cancer The compositions that relates to giving the compound including any or multiple Formulas I or I ' of object effective dose also combines selected from following Chemotherapeutics: 5-FUD, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, Changchun Alkali, bevacizumab, Cetuximab, interferon-' alpha ', interleukin II or erlotinib.
In the 23rd aspect, the invention provides disease or the method for disease for the treatment of in object in need, its By give the compound any one or more of described herein of subject effective dose, the prodrug of this compound or This compound or the pharmaceutically acceptable salt of prodrug or this compound or prodrug pharmaceutically acceptable Preparation and carry out.Compound can be can be maybe individually the part of compositions.In one embodiment, the present invention carries Supplied to treat disease or the method for disease in object in need, its by give subject effective dose any one or Multiple compound described herein, the prodrug of this compound, this compound or prodrug pharmaceutically acceptable Salt or this compound or the pharmaceutically acceptable preparation of prodrug and combine this disease or disease one or more its Its suitable therapy and carry out.
In twenty-fourth aspect, the invention provides and include compound described herein or the test kit of a combination thereof thing.? In some embodiments, compound or compositions are packaged in such as capsule, bottle, flask, and it can be packaged in example further In box, big envelope or bag；Described compound or compositions are by FDA (Food and Drug Adminstration) (U.S.Food and Drug Administration) or similar administrative organization (regulatory agency) approval be administered to mammal, such as people；Institute State compound or compositions goes through to be administered to mammal, such as people, for the disease that Fns and/or Kit is protein kinase mediated Or disease；Test kit of the present invention includes that written operation instructions and/or compound or compositions are suitable to or ratify be administered to suckling Animal such as people is for other instruction of disease protein kinase mediated for Fms and/or Kit or disease；And, compound or combination Thing can be packed with unit dose or one-pack type, such as single dose pill, capsule etc..
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Bright provide at object in need, (such as mammal, such as the mankind, other primates, sport animals (sports Animal), commercial object animal such as cattle, farm-animals such as horse or house pet such as Canis familiaris L. and cat) the middle disease treating Kit-mediation Disease or disease, such as, be characterized as disease or the method for disease of abnormal Kit activity (such as kinase activity).At some embodiments In, the inventive method can include to the disease suffering from c-kit-mediation or the object of disease or be in disease or the disease that c-kit-mediates One or more compounds as herein described of subject effective amounts under the risk of disease.In one embodiment, Kit is situated between The disease led be selected from malignant tumor, its include but not limited to mastocytoma, small cell lung cancer, nonsmall-cell lung cancer (NSCLC), Carcinoma of testis, cancer of pancreas, breast carcinoma, Meike ear Schwann Cells cancer, female reproductive tract cancer, the sarcoma of neuroectodermal origin, rectal cancer, Cancer in situ, gastrointestinal stromal tumor (GIST), tumor-blood-vessel growth, glioblastoma multiforme, neuroastrocytoma, neuroblast Tumor, neurofibromatosis (including that the schwann's tumor relevant with neurofibroma is formed), acute myeloid leukemia, acute pouring Bar leukemia, chronic granulocytic leukemia, mastocytosis, melanoma and dog mastocytoma；Cardiovascular Disease, it includes but not limited to atherosclerosis, cardiomyopathy, heart failure, pulmonary hypertension and pulmonary fibrosis；Inflammatory and Autoimmunity indication, it includes but not limited to allergy, anaphylaxis, asthma, rheumatoid arthritis, allergic rhinitis, multiple Property sclerosis, inflammatory bowel disease, graft-rejection, hypereosinophilia, urticaria and dermatitis；Gastrointestinal indication bag Include but be not limited to gastroesophageal reflux disease (GERD), esophagitis and gastrointestinal ulceration；Adaptation of eye disease, it includes but not limited to wink Element layer inflammation and retinitis；And nervous system indication, it includes but not limited to migraine.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Bright provide for object in need (such as mammal, as the mankind, other primates, sport animals, commercial object move Thing such as cattle, farm-animals such as horse or house pet such as Canis familiaris L. and cat) in treatment Fms-mediation disease or disease, such as feature Disease or the method for disease for abnormal Fms activity (such as kinase activity).In some embodiments, the inventive method can be wrapped Include to suffer from Fms-mediation disease the object of disease or be in Fms-mediation disease or disease risk under object use One or more of effective dose compound as herein described.In one embodiment, Fms mediation disease selected from inflammatory and from Body immunity indication, it includes but not limited to rheumatoid arthritis, osteoarthritis, arthritic psoriasis, psoriasis, skin Spondylitis scorching, mandatory, polymyositis, dermatomyositis, systemic sclerosis, idiopathic juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, polymyalgia rheumatica, Si Ye Ge Lunshi is sick, langerhans' cells histiocytosis (Langerhan ' s cell histiocytosis) (LCH), Si Di Er Shi disease, inflammatory bowel disease, ulcerative colitis, Crohn disease, systemic lupus erythematosis (SLE), immunity blood are little Plate minimizing property purpura (ITP), the preparation of autoplastic spinal cord, graft-rejection, chronic obstructive pulmonary disease (COPD), lung qi Swollen, river Ji Shi disease, blood swallow syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis and tremulous pulse medicated porridge Sample hardens；Metabolic disease, its include but not limited to type i diabetes, type ii diabetes, insulin resistance, hyperglycemia, obesity and Lipolysis；Bone structure, mineralising and bone formation and the disease of absorption, it includes but not limited to osteoporosis, osteotrophy not Good, risk of bone fracture increase, Paget, hypercalcemia, the osteolysis (such as myelitis) of infection mediation and Periprosthetic or The osteolysis of wear debris mediation；Kidney and genitourinary disorders, include but not limited to endometriosis, nephritis (such as kidney Bead nephritis, interstitial nephritis, lupus nephritis), renal tubular necrosis, renal complication (such as diabetes that diabetes are relevant Nephropathy) and renal hypertrophy；Nervous system disease, includes but not limited to demyelination (such as multiple sclerosis, summer horse figure three Syndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic Demyelinating Polyneuropathy, other demyelination Disease, apoplexy, Alzheimer and parkinson；Pain, it includes but not limited to chronic pain, acute pain, inflammation Property pain, neuropathic pain, osteodynia；Malignant tumor, it includes but not limited to multiple myeloma, acute myeloid leukemia (AML), chronic granulocytic leukemia (CML), pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, breast carcinoma, ovarian cancer, neuroblast Tumor, sarcoma, osteosarcoma, giant cell tumor (giant cell tumor of such as bone, the giant cell tumor (TGCT) of stndon sheath), pigmented villonodular Synovitis (PVNS), tumor-blood-vessel growth, melanoma, glioblastoma multiforme, glioma, central nervous system Other onch-tumor metastasis to other tissue, osteolytic Bone tumour and other chronic myeloproliferative disease such as myelofibrosis； Vasculitis, it includes but not limited to collagen vascular disease (collagen vascular disease), polyarteritis nodosa, shellfish Cut Te Shi disease, sarcoidosis, familial Mediterranean fever, churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, high iS-One Arteritis；Adaptation of eye disease, its include but not limited to degeneration of macula that uveitis, scleritis, retinitis, age are relevant, Choroidal neovascularization, diabetic retinopathy；Genetic diseases, it includes but not limited to macrognathia, neurofibroma；Infect disease Sick indication, it includes but not limited to the infection relevant with human immunodeficiency virus, hepatitis B virus, hepatitis C virus Poison, Human granulocytic anaplasmosis (human granulocytic anaplasmosis)；Lysosomal storage disorder, it include but It is not limited to familial splenic anemia, Fabry disease, niemann-Pick disease；Gastrointestinal indication, it includes but not limited to liver cirrhosis；Lung adapts to Disease, it includes but not limited to pulmonary fibrosis, acute lung injury (acute lung injury) (such as air-conditioning cause, cigarette or poison Element causes)；And operative indication, it includes but not limited to (cardiopulmonary) bypass, vascular surgery and vascular graft (vascular grafts)。
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Invention provides at object in need, (such as mammal, such as the mankind, other primates, sport animals, commercial object Animal such as cattle, farm-animals such as horse or house pet such as Canis familiaris L. and cat) in treatment Fms and Kit mediation disease or disease, example As being characterized as abnormal Fms activity and the disease of Kit activity (such as kinase activity) or the method for disease.At some embodiments In, the inventive method can include the disease suffering from Fms and Kit mediation or the object of disease or be in the disease of Fms and Kit mediation One or more compounds described herein of object effective dose under the risk of disease or disease.In one embodiment, Fms and The disease of Kit mediation is selected from rheumatoid arthritis, osteoarthritis, arthritic psoriasis, psoriasis, dermatitis, allergy, allergy Disease, asthma, allergic rhinitis, mandatory spondylitis, polymyositis, dermatomyositis, systemic sclerosis, idiopathic juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, Polymyalgia rheumatica, sjogren's disease, langerhans' cells histiocytosis, Si Diershi disease, inflammatory bowel disease, Ulcerative colitis, Crohn disease, systemic lupus erythematosis, immunologic thrombocytopenic purpura, autoplastic ridge Marrow preparation, graft-rejection, chronic obstructive pulmonary disease, emphysema, river Ji Shi disease, blood phagocytosis syndrome, multicentricity net Shape histocytomatosis, hypereosinophilia and urticaria type i diabetes, type ii diabetes, insulin resistance, high blood Sugar, obesity and lipolysis, osteoporosis, osteodystrophy, risk of bone fracture increase, Paget, hypercalcemia, infection The osteolysis of mediation and Periprosthetic or the osteolysis of wear debris mediation, endometriosis, nephritis, renal tubules are bad Extremely, diabetes are relevant renal complication and renal hypertrophy, multiple sclerosis, summer horse figure three syndrome, amyotrophy funiculus lateralis Sclerosis, myasthenia gravis, chronic Demyelinating Polyneuropathy, other demyelination, apoplexy, Alzheimer and Parkinson, acute pain, neuropathic pain, inflammatory pain, chronic pain, migraine, multiple myeloma, acute lymphoblastic Property leukemia, acute myeloid leukemia, chronic granulocytic leukemia, mastocytoma, dog mastocytoma, pulmonary carcinoma, Carcinoma of testis, cancer of pancreas, carcinoma of prostate, breast carcinoma, ovarian cancer, Meike ear Schwann Cells cancer, female reproductive tract cancer, rectal cancer, in situ Cancer, gastrointestinal stromal tumor (gastrointestinal stromal tumor), tumor-blood-vessel growth, neuroastrocytoma, Neuroblastoma, sarcoma, osteosarcoma, the sarcoma of neuroectodermal origin, the giant cell tumor of bone, the giant cell tumor of stndon sheath, color Element pigmented villonodular synovitis, melanoma, glioblastoma multiforme, glioblastoma multiforme, glioma, maincenter god Through other tumor of system, neurofibroma (including that the schwann's tumor relevant with neurofibroma is formed), mastocytosis, Neoplasm metastasis is to other tissue, osteolytic Bone tumour and other chronic myeloproliferative disease such as myelofibrosis, Collagen vascular Disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familial Mediterranean fever, churg-Strauss vasculitis, Temporal Artery Inflammation, giant cell arteritis, high iS-One arteritis, uveitis, scleritis, retinitis, age relevant degeneration of macula, arteries and veins The infection relevant with human immunodeficiency virus of network film neovascularization, diabetic retinopathy, macrognathia, neurofibroma, second Hepatitis virus, hepatitis C virus, Human granulocytic anaplasmosis, familial splenic anemia, Fabry disease, niemann-Pick disease, liver are hard Change, gastroesophageal reflux disease, esophagitis and gastrointestinal ulceration, pulmonary fibrosis, acute lung injury, bypass, vascular surgery and blood Pipe grafting, atherosclerosis, cardiomyopathy, heart failure and pulmonary hypertension.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Invention provides at object in need, (such as mammal, such as the mankind, other primates, sport animals, commercial object Animal such as cattle, farm-animals such as horse or house pet such as Canis familiaris L. and cat) in treatment Fms and Flt-3 mediation disease or disease, Such as it is characterized as abnormal Fms activity and the disease of flt-3 activity (such as kinase activity) or the method for disease.Some embodiment party In formula, the inventive method can include disease or the object of disease of suffering from Fms and Flt-3 mediation or be in Fms and Flt-3 Jie One or more compounds described herein of object effective dose under the disease led or the risk of disease.At an embodiment In, the disease of Fms and Flt-3 mediation is acute myeloid leukemia.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to suffering from the disease or the object in need of disease or in need under being in the risk of disease or disease One or more of subject effective amounts compound described herein, described disease or disease are selected from rheumatoid arthritis, bone Arthritis, osteoporosis, periprosthetic osteolysis, systemic sclerosis, demyelination, multiple sclerosis, summer horse Figure three syndrome, amyotrophic lateral sclerosis, Alzheimer, parkinson, ulcerative colitis, Chron Disease, immunologic thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, autoplastic spinal cord prepare, move Plant rejection, glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, diabetic nephropathy, renal hypertrophy, I Patients with type Ⅰ DM, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple bone marrow Tumor, metastatic breast cancer, carcinoma of prostate, cancer of pancreas, pulmonary carcinoma, ovarian cancer, glioma, glioblastoma multiforme, nerve fiber Tumor, osteolytic Bone tumour, brain metastes, gastrointestinal stromal tumor and giant cell tumor.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to suffering from the disease or the object in need of disease or in need under being in the risk of disease or disease One or more of subject effective amounts compound described herein, described disease or disease are selected from rheumatoid arthritis, gastrointestinal Road mesenchymoma, melanoma and neurofibroma, wherein compound is the inhibitor of Kit, i.e. has generally acknowledged Kit kinases such as and lives Property test in measure less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than 1nM IC50。
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to suffering from the disease or the object in need of disease or in need under being in the risk of disease or disease One or more of subject effective amounts compound described herein, described disease or disease are selected from multiple sclerosis, colloid Blastoma, Alzheimer, parkinson, rheumatoid arthritis, osteoarthritis, atherosclerosis, systematicness Lupus erythematosus, glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, diabetic nephropathy and renal hypertrophy, its Middle compound is Fms selective depressant, i.e. have as in generally acknowledged Fms Kinase activity assays measure less than 500nM, be less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50, and when at suitable generally acknowledged Kit ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ will be had when Kinase activity assays measures 90, the kinase whose IC of Kit of also ＞ 10050Divided by the kinase whose IC of Fms50Ratio；In some embodiments, compound is relative to removing The protein kinase of Kit is also selective, so that another kinase whose IC of considerably assessing50Divided by the kinase whose IC of Fms50's Than ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other albumen Kinases includes but not limited to Flt-3, CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to suffering from the disease or the object in need of disease or in need under being in the risk of disease or disease One or more of subject effective amounts compound described herein, described disease or disease are selected from multiple sclerosis, colloid Blastoma, Alzheimer and parkinson, wherein compound is Fms selective depressant, i.e. has as generally acknowledged Fms Kinase activity assays in measure less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, be less than 5nM or the IC less than 1nM50And when in suitable generally acknowledged Kit Kinase activity assays measure time will have ＞ 20, and also ＞ 30, The kinase whose IC of Kit of also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 10050Kinase whose divided by Fms IC50Ratio, and wherein compound passes through blood brain barrier effectively；In some embodiments, compound is relative to except Kit Protein kinase be also selective so that another the kinase whose IC considerably assessed50Divided by the kinase whose IC of Fms50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase Include but not limited to Flt-3, CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to suffering from the disease or the object in need of disease or in need under being in the risk of disease or disease One or more of subject effective amounts compound described herein, described disease or disease are closed selected from rheumatoid arthritis, bone Joint inflammation, atherosclerosis, systemic lupus erythematosus (sle), glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, Diabetic nephropathy and renal hypertrophy, wherein compound is Fms selective depressant, i.e. has such as generally acknowledged Fms kinase activity examination Test middle mensuration less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than 1nM IC50And will have when measuring in suitable generally acknowledged Kit Kinase activity assays ＞ 20, also ＞ 30, also ＞ 40, go back ＞ 50, The kinase whose IC of Kit of also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 10050Divided by the kinase whose IC of Fms50Ratio, and its Middle compound not operatively passes through blood brain barrier；In some embodiments, compound is relative to the protein kinase except Kit also It is selective, so that another the kinase whose IC considerably assessed50Divided by the kinase whose IC of Fms50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase includes but not limited to Flt-3, CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to suffering from the disease or the object in need of disease or in need under being in the risk of disease or disease One or more of subject effective amounts compound described herein, described disease or disease are selected from metastatic breast cancer, prostatitis Adenocarcinoma, multiple myeloma, melanoma, brain metastes, neurofibroma, gastrointestinal stromal tumor, rheumatoid arthritis and multiple Property sclerosis, wherein compound is dual Fms/Kit inhibitor, i.e. have as in generally acknowledged Fms Kinase activity assays measure Less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50, and will tool Just like suitable generally acknowledged Kit Kinase activity assays measures less than 500nM, less than 100nM, less than 50nM, less than 20nM, little In 10nM, less than 5nM or less than the IC of 1nM50, the wherein kinase whose IC of Kit50Divided by the kinase whose IC of Fms50Ratio 20 to 0.05, Also have 10 to 0.1, also have in the range of 5 to 0.2；In some embodiments, compound is relative to except the protein kinase of Kit Also it is selective, so that another the kinase whose IC considerably assessed50Divided by the kinase whose IC of Fms50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase includes but not limited to CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.
Relating to in one or more compounds for treating diseases described herein or the aspect of disease and embodiment, this Inventive method can include to the object in need suffering from acute myeloid leukemia or be in acute myeloid leukemia One or more compounds described herein of subject effective amounts in need under risk, wherein compound is dual Fms/ Flt-3 inhibitor, i.e. have as in generally acknowledged Fms Kinase activity assays measure less than 500nM, less than 100nM, be less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50And live having suitable generally acknowledged Flt-3 kinases such as Property test in measure less than 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than 1nM IC50, the wherein kinase whose IC of Flt-350Divided by the kinase whose IC of Fms50Ratio 20 to 0.05, also have 10 to 0.1, also have 5 to In the range of 0.2；In some embodiments, compound is also selective relative to the protein kinase except Flt-3, so that Another the kinase whose IC considerably assessed50Divided by the kinase whose IC of Fms50Ratio ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100, wherein other protein kinase includes but not limited to that CSK, Insulin receptor INSR swash Enzyme, AMPK, PDGFR or VEGFR.
In the 25th aspect, one or more compounds as herein described or compositions can be used for preparation for treating The disease of Kit-mediation or the medicine of disease, the disease of described Kit-mediation or disease are selected from malignant tumor, and it includes but does not limits In mastocytoma, small cell lung cancer, non-small cell lung cancer, carcinoma of testis, cancer of pancreas, breast carcinoma, Meike ear Schwann Cells cancer, female Sexual reproduction road cancer, the sarcoma of neuroectodermal origin, rectal cancer, cancer in situ, gastrointestinal stromal tumor, tumor-blood-vessel growth, colloid Blastoma, neuroastrocytoma, neuroblastoma, neurofibroma (include the perhaps Wang Shi relevant with neurofibroma Neoplasia), acute myeloid leukemia, acute lymphatic leukemia, chronic granulocytic leukemia, Mastocytosis Disease, melanoma and dog mastocytoma；Cardiovascular disease, it includes but not limited to that atherosclerosis, cardiomyopathy, heart decline Exhaust, pulmonary hypertension and pulmonary fibrosis；Inflammatory and autoimmunity indication, it includes but not limited to allergy, anaphylaxis, heavy breathing Breathe heavily, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel disease, graft-rejection, eosinophil Increase disease, urticaria and dermatitis；Gastrointestinal indication, it includes but not limited to that gastroesophageal reflux disease, esophagitis and gastrointestinal tract are burst Infections；Adaptation of eye disease, it includes but not limited to uveitis and retinitis；And nervous system indication, it include but not It is limited to migraine.The invention further provides for treat disease or the one of disease or many of Kit-as herein described mediation Plant compound as herein described or compositions.
In the 26th aspect, one or more compounds as herein described can be used for preparing for treating Fms-mediation Disease or the medicine of disease, the disease of described Fms-mediation or disease are selected from inflammatory and autoimmunity indication, and it includes But be not limited to rheumatoid arthritis, osteoarthritis, arthritic psoriasis, psoriasis, dermatitis, mandatory spondylitis, polymyositis, Dermatomyositis, systemic sclerosis, idiopathic juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, polymyalgia rheumatica, sjogren's disease, langerhans' cells group Knit cytosis sick (LCH), Si Diershi disease, inflammatory bowel disease, ulcerative colitis, Crohn disease, systematicness erythema Property lupus (SLE), immunologic thrombocytopenic purpura (ITP), the preparation of autoplastic spinal cord, graft-rejection, chronic Obstructive pulmonary disease (COPD), emphysema, river Ji Shi are sick, blood phagocytosis syndrome (macrophage activation syndrome), multicentricity Reticulohistiocytosis and atherosclerosis；Metabolic disease, it includes but not limited to type i diabetes, type ii diabetes, pancreas Island element resistance, hyperglycemia, obesity and lipolysis；Bone structure, mineralising and bone formation and the disease of absorption, it includes but does not limits In osteoporosis, osteodystrophy, risk of bone fracture increase, Paget, hypercalcemia, the osteolysis (example of infection mediation Such as myelitis) and Periprosthetic or wear debris mediation osteolysis；Kidney and genitourinary disorders, it includes but not limited to son Endometriosis, nephritis (such as glomerulonephritis, interstitial nephritis, lupus nephritis), renal tubular necrosis, diabetes are correlated with Renal complication (such as diabetic nephropathy) and renal hypertrophy；Nervous system disease, it includes but not limited to demyelination (example Such as multiple sclerosis, summer horse figure three syndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic demyelination Polyneuropathy, other demyelination, apoplexy, Alzheimer and parkinson；Pain, it includes but does not limits In chronic pain, acute pain, inflammatory pain, neuropathic pain, osteodynia；Malignant tumor, it includes but not limited to multiple bone Myeloma, acute myeloid leukemia (AML), chronic granulocytic leukemia (CML), pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, breast Adenocarcinoma, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant cell tumor (giant cell tumor of such as bone, the giant cell tumor of stndon sheath (TGCT)), pigmented villonodular synovitis (PVNS), tumor-blood-vessel growth, melanoma, glioblastoma multiforme, Glioma, central nervous system other onch-tumor metastasis to other tissue, osteolytic Bone tumour and other Chronic Myeloid Proliferative disease such as myelofibrosis；Vasculitis, it includes but not limited to collagen vascular disease, polyarteritis nodosa, Bei Qiete Family name's disease, sarcoidosis, familial Mediterranean fever, churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, high iS-One tremulous pulse Scorching；Adaptation of eye disease, it includes but not limited to degeneration of macula, the venation that uveitis, scleritis, retinitis, age are relevant Film neovascularization, diabetic retinopathy；Genetic diseases, it includes but not limited to macrognathia, neurofibroma；Catch suitable Answering disease, it includes but not limited to the infection relevant with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, people Granulocyte anaplasmosis；Lysosomal storage disorder, it includes but not limited to familial splenic anemia, Fabry disease, niemann-Pick disease； Gastrointestinal indication, it includes but not limited to liver cirrhosis；Lung indication, it includes but not limited to pulmonary fibrosis, acute lung injury (example That cause such as air-conditioning, cigarette or toxin cause)；And operative indication, it includes but not limited to (cardiopulmonary) bypass, blood vessel hands Art and vascular graft.The invention further provides for treat disease or the one of disease or many of Fms-described herein mediation Plant compound as herein described or compositions.
In 27 aspects, one or more compounds as herein described can be used for preparing for treating Fms-mediation With disease or the medicine of disease of Kit-mediation, disease or the disease with Kit-mediation of described Fms-mediation are closed selected from rheumatoid Joint inflammation, osteoarthritis, arthritic psoriasis, psoriasis, dermatitis, allergy, anaphylaxis, asthma, allergic rhinitis, mandatory ridge Post inflammation, polymyositis, dermatomyositis, systemic sclerosis, idiopathic juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, polymyalgia rheumatica, sjogren's disease, bright Ge Han Schwann Cells histiocytosis, Si Diershi disease, inflammatory bowel disease, ulcerative colitis, Crohn disease, system Property lupus erythematosus, immunologic thrombocytopenic purpura, the preparation of autoplastic spinal cord, graft-rejection, chronic obstruction Property lung disease, emphysema, river Ji Shi be sick, blood phagocytosis syndrome, multicentric reticulohistiocytosis, eosinophilia Disease and urticaria type i diabetes, type ii diabetes, insulin resistance, hyperglycemia, obesity and lipolysis, osteoporosis, The increase of osteodystrophy, risk of bone fracture, Paget, hypercalcemia, the osteolysis of infection mediation and Periprosthetic or abrasion Renal complication that the osteolysis of fragment mediation, endometriosis, nephritis, renal tubular necrosis, diabetes are relevant and kidney Hypertrophy, multiple sclerosis, summer horse figure three syndrome, amyotrophic lateral sclerosis, myasthenia gravis, chronic demyelination are multiple Property neuropathy, other demyelination, apoplexy, Alzheimer and parkinson, acute pain, neuropathic pain, Inflammatory pain, chronic pain, migraine, multiple myeloma, acute lymphatic leukemia, acute myeloid leukemia, slow Property myelocytic leukemia, mastocytoma, dog mastocytoma, pulmonary carcinoma, carcinoma of testis, cancer of pancreas, carcinoma of prostate, breast carcinoma, Ovarian cancer, Meike ear Schwann Cells cancer, female reproductive tract cancer, rectal cancer, cancer in situ, gastrointestinal stromal tumor, tumor-blood-vessel growth, star Shape glioma, neuroblastoma, sarcoma, osteosarcoma, the sarcoma of neuroectodermal origin, the giant cell tumor of bone, stndon sheath Giant cell tumor, pigmented villonodular synovitis, melanoma, glioblastoma multiforme, glioblastoma multiforme, nerve Glioma, other tumor of central nervous system, neurofibroma (including that the schwann's tumor relevant with neurofibroma is formed), fertilizer Mastocytosis, neoplasm metastasis are fine to other tissue, osteolytic Bone tumour and other chronic myeloproliferative disease such as bone marrow Dimensionization, collagen vascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis, familial Mediterranean fever, Qiu-execute Er Shi blood Guan Yan, temporal arteritis, giant cell arteritis, high iS-One arteritis, uveitis, scleritis, retinitis, age are correlated with Degeneration of macula, choroidal neovascularization, diabetic retinopathy, macrognathia, neurofibroma have with human immunodeficiency virus The infection of pass, hepatitis B virus, hepatitis C virus, Human granulocytic anaplasmosis, familial splenic anemia, Fabry disease, Ni-skin Er Shi disease, liver cirrhosis, gastroesophageal reflux disease, esophagitis and gastrointestinal ulceration, pulmonary fibrosis, acute lung injury, bypass, blood Pipe operation and vascular graft, atherosclerosis, cardiomyopathy, heart failure and pulmonary hypertension.The present invention further provides For treat Fms-described herein mediation and the disease of Kit-mediation or one or more chemical combination as herein described of disease Thing or compositions.
In twenty-eighth aspect, one or more compounds as herein described can be used for preparation for treating disease or disease The medicine of disease, described disease or disease are molten selected from rheumatoid arthritis, osteoarthritis, osteoporosis, periprosthetic bone Solution, systemic sclerosis, demyelination, multiple sclerosis, summer horse figure three syndrome, amyotrophic lateral sclerosis funiculus lateralis medullae spinalis are hard Change, Alzheimer, parkinson, ulcerative colitis, Crohn disease, immunologic thrombocytopenic purpura, Autoplastic spinal cord preparation, graft-rejection, glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, The white blood of diabetic nephropathy, renal hypertrophy, type i diabetes, acute pain, inflammatory pain, neuropathic pain, acute myelocytic Disease, melanoma, multiple myeloma, metastatic breast cancer, carcinoma of prostate, cancer of pancreas, pulmonary carcinoma, ovarian cancer, glioma, Glioblastoma multiforme, neurofibroma, osteolytic Bone tumour, brain metastes, gastrointestinal stromal tumor and giant cell tumor.
In the 29th aspect, one or more compounds as herein described for Kit inhibitor can be used for preparation use In treatment rheumatoid arthritis, gastrointestinal stromal tumor, melanoma or the medicine of neurofibroma.
In 30 aspects, one or more compounds as herein described for Fms selective depressant can be used for preparing For treating multiple sclerosis, glioblastoma multiforme, Alzheimer, parkinson, rheumatoid arthritis, bone pass Joint inflammation, atherosclerosis, systemic lupus erythematosus (sle), glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, Diabetic nephropathy or the medicine of renal hypertrophy.
In the 31st aspect, for effectively passing through as herein described the one of the Fms selective depressant of blood brain barrier Plant or multiple compounds can be used for preparation for treating multiple sclerosis, glioblastoma multiforme, Alzheimer or handkerchief The medicine that gold Sen Shi is sick.
In the 32nd aspect, for not operatively passing through the as herein described of the Fms selective depressant of blood brain barrier One or more compounds can be used for preparation for treating rheumatoid arthritis, osteoarthritis, atherosclerosis, systemic red The medicine of yabbi skin ulcer, glomerulonephritis, interstitial nephritis, lupus nephritis, renal tubular necrosis, diabetic nephropathy or renal hypertrophy Thing.
In the 33rd aspect, one or more compounds as herein described for dual Fms/Kit inhibitor can be used In preparation be used for treating metastatic breast cancer, carcinoma of prostate, multiple myeloma, melanoma, acute myeloid leukemia, The medicine of brain metastes, neurofibroma, gastrointestinal stromal tumor, rheumatoid arthritis or multiple sclerosis.
In the 34th aspect, one or more compounds as herein described for dual Fms/Flt-3 inhibitor can For preparation for treating the medicine of acute myeloid leukemia.
In the 35th aspect, the invention provides the intermediate compound of Formula V:
Or its stereoisomer,
Wherein:
P2It it is amido protecting group；
Ar is selected from:
Wherein The Ar and-CH of expression I2-junction point and whereinThe junction point of the Ar and-NH-of expression I；
R1、R2、R3And R4Each is independently selected from-H, halogen, low-carbon alkyl, the low-carbon alkyl of halogen substiuted, alkoxyl Substituted low-carbon alkyl, cycloalkyl amino ,-CN ,-O-R40、-S(O)2-R41、-S(O)2-N(H)-R42、-N(H)-R42、-N (R42)2With-N (H)-S (O)2-R43, condition is R1、R2、R3And R4In at least two be-H and R1、R2、R3And R4In one Non-hydrogen,
Wherein:
R40It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；
R41、R42And R43It it is low-carbon alkyl.In some embodiments, variables A r, R7、R8、R9、R1、R2、R3And R4Such as this Literary composition definition.
In the 36th aspect, the invention provides formula I ' the method for compound:
The method is included under conditions of the compound that be enough to be formed Formulas I with the compound of Formula V:
The compound of contact formula IV:
, wherein:
P1And P2Each is amido protecting group independently；
X is H or halogen；
Ar is selected from:
Wherein The Ar and-CH of expression I2-junction point and whereinThe junction point of the Ar and-NH-of expression I；
R1、R2、R3And R4Each replaces independently selected from-H, low-carbon alkyl, the low-carbon alkyl of halogen substiuted, alkoxyl Low-carbon alkyl, cycloalkyl amino ,-CN ,-O-R40、-S(O)2-R41、-S(O)2-N(H)-R42、-N(H)-R42,-N (R42)2With- N(H)-S(O)2-R43, condition is R1、R2、R3And R4In at least two be-H and R1、R2、R3And R4In a non-hydrogen,
Wherein:
R40It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl；
R41、R42And R43It it is low-carbon alkyl；
R5Selected from-H ,-F ,-Cl ,-Br, low-carbon alkyl, the alkyl of halogen substiuted, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkanes Base, phenyl, pyrazolyl ,-CN ,-O-R10、-C(O)-N(H)-R11,-C (O)-O-R11、-S(O)2-R12、-S(O)2-N(H)-R11、- N(H)-C(O)-R12With-N (H)-S (O)2-R12, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R6Selected from H, halogen, low-carbon alkyl, the alkyl of halogen substiuted, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, Pyrazolyl ,-CN ,-O-R13、-C(O)-N(H)-R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14、-N(H)-C (O)-R15With-N (H)-S (O)2-R15, wherein pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl；
R7It is H, halogen or low-carbon alkyl；
R8It is H, halogen, low-carbon alkyl or low-carbon alkoxy；
R9It is H or halogen；
R10And R13Be independently-H, low-carbon alkyl, with-O-CH3Substituted low-carbon alkyl, with the substituted low-carbon (LC) of dialkylamine Alkyl or with the substituted low-carbon alkyl of Heterocyclylalkyl；
R11And R14It is hydrogen or low-carbon alkyl independently；And
R12And R15Each is low-carbon alkyl independently, condition be compound be not in table 1 propose those.P1And P2It is Amido protecting group as herein described.In one embodiment, P2It it is tertbutyloxycarbonyl.In another embodiment, P1It is benzene Base sulfonyl.In one embodiment, by formula IV compound and Formula V in the presence of highly basic such as alkali metal hydroxide The reaction of compound carries out described contact.Exemplary alkali metal hydroxide includes NaOH, KOH and LiOH.Another embodiment party In formula, contact includes the Grignard reagent of shape compound of formula IV and makes the Grignard reagent of formula IV compound and Formula V compound enter one Step reaction.In another embodiment, contact makes formula IV compound react with Formula V compound in the presence of being included in palladium complex. In some embodiments, variable R5And R6As defined in any of the above embodiment of compound of formula I.Some embodiment party In formula, variable R1、R2、R3And R4As defined in any of the above embodiment of compound of formula I.
In some embodiments, the invention provides preparation Formula II ' the method for compound:
The method is included in and be enough to form Formula II ' compound under conditions of with the compound of Formula VII:
The compound of contact Formula IV:
, wherein P1And P2Each is amido protecting group independently；X is H or halogen；R6Selected from H, halogen, lower alkanes Base, the alkyl of halogen substiuted, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N (H)-R14、-C(O)-O-R14、-S(O)2-R15,-S (O)2-N(H)-R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, its Middle pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl.R16、R17、R18And R19Each is independently selected from H, halogen, low The substituted low-carbon alkyl of carbon alkyl, low-carbon alkoxy, halogen ,-OR20, or the substituted low-carbon alkyl of alkoxyl.An embodiment party In formula, R6It it is low-carbon alkyl.In another embodiment, R6It is CH3Or CN.In another embodiment, R6It is methyl, ethyl Or propyl group.P1And P2It it is amido protecting group as herein described.In one embodiment, P2It it is tertbutyloxycarbonyl.Real at another Execute in mode, P1It it is phenyl sulfonyl.In one embodiment, by making in the presence of highly basic such as alkali metal hydroxide Formula IV compound carries out described contact with the reaction of Formula VII compound.Exemplary alkali metal hydroxide includes NaOH, KOH And LiOH.In another embodiment, contact includes forming the Grignard reagent of Formula IV compound and making the lattice of Formula IV compound Family name's reagent reacts further with Formula VII compound.
In some embodiments, formula III is prepared in offer of the present invention ' the method for compound:
The method is included in and be enough to form formula III ' under conditions of compound with the compound of Formula VIII:
The compound of contact Formula IV
, wherein P1And P2Each is amido protecting group independently；X is H or halogen；R6Selected from H, halogen, lower alkanes Base, the alkyl of halogen substiuted, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, phenyl, pyrazolyl ,-CN ,-O-R13、-C(O)-N (H)-R14、-C(O)-O-R14、-S(O)2-R15、-S(O)2-N(H)-R14、-N(H)-C(O)-R15With-N (H)-S (O)2-R15, its Middle pyrazolyl is optionally replaced by low-carbon alkyl or Heterocyclylalkyl.R16、R17、R18And R19Each is independently selected from H, halogen, low The substituted low-carbon alkyl of carbon alkyl, low-carbon alkoxy, halogen ,-OR20, or the substituted low-carbon alkyl of alkoxyl.An embodiment party In formula, R6It it is low-carbon alkyl.In another embodiment, R6It is CH3Or CN.In another embodiment, R6It is methyl, ethyl Or propyl group.P1And P2It it is amido protecting group as herein described.In one embodiment, P2It it is tertbutyloxycarbonyl.Real at another Execute in mode, P1It it is phenyl sulfonyl.In one embodiment, by making in the presence of highly basic such as alkali metal hydroxide Formula IV compound reacts with Formula VIII compound and carries out described contact.Exemplary alkali metal hydroxide include NaOH, KOH and LiOH.In another embodiment, contact includes forming the Grignard reagent of Formula IV compound and making the grignard of Formula IV compound try Agent is reacted further with Formula VIII compound.
Be will be apparent from by detailed description of the invention below and claims, other side and embodiment.
Detailed Description Of The Invention
Unless otherwise expressly stated, as used herein, use following definitions:
Point out on the contrary unless clear and definite, in formula described herein in the structure provided or relevant to described structure The all atoms pointed out in the definition of variable are intended to include its any isotope.Should be appreciated that for any given former Son, isotope substantially to exist according to they naturally occurring ratios, or can use synthesis side well known by persons skilled in the art Method, relative to one or more isotopes, one or more concrete atoms can be reinforced.Thus, hydrogen includes such as1H、2H、3H； Carbon includes such as11C、12C、13C、14C；Oxygen includes such as16O、17O、18O；Nitrogen includes such as13N、14N、15N；Sulfur includes such as32S 、33S、34S、35S、36S、37S、38S；Fluorine includes such as17F、18F、19F；Chlorine includes such as35Cl、36Cl、37Cl、38Cl、39Cl；And class Like situation.
" halogen " or " halogen " refers to all halogens, i.e. chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).
" low-carbon alkyl ", alone or in combination, refer to comprise 1 to 6 carbon atom (unless limited otherwise) derived from alkane The group of hydrocarbon, it includes straight chained alkyl or branched alkyl.In many embodiments, low-carbon alkyl is to comprise 1-6,1-4 or 1-2 The straight chained alkyl of individual carbon atom or branched alkyl, such as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group etc..Unless additionally referred to Going out, low-carbon alkyl can be as described herein the most one or more, it is preferable that 1,2,3,4 or 5 substituent groups, it is possible to To be that 1,2 or 3 substituent groups replace, wherein substituent group is as shown.Furthermore, it is possible to be substituted on any available atom connection With the compound that offer is stable.It is substituted low that such as " the substituted low-carbon alkyl of halogen " refers to one or more halogen atom Carbon alkyl group, the most preferably low-carbon alkyl by 1,2,3,4 or 5 halogen atoms, can also be 1,2 or 3 halogen atoms Replace.Furthermore, it is possible to be substituted on any available atom the compound connecting to provide stable.Such as " the substituted low-carbon (LC) of fluorine Alkyl " refer to one or more fluorine atom substituted low-carbon alkyl group, such as perfluoroalkyl, the most preferably lower alkanes Base by 1,2,3,4 or 5 fluorine atoms, can also be that 1,2 or 3 fluorine atoms replace.Exemplary fluorine substituted low-carbon alkyl bag Include but be not limited to CF3、CF2CF3、CH2CF3Deng.Should be appreciated that replacement is the most feasible and connects on any available atom With the compound that offer is stable.
" low-carbon alkoxy " refer to those low-carbon alkyl groups of limiting herein by oxygen atom be connected to molecule other In part.Representational alkoxy base includes methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, positive penta oxygen Base, epoxide in positive heptan etc. and their isomer.
" low carbon chain thiazolinyl ", alone or in combination, refer to containing 2-6 carbon atom (unless limited otherwise) and at least 1, Preferably 1-3, the straight or branched hydrocarbon of more preferably 1-2, most preferably 1 carbon-carbon double bond.Carbon-carbon double bond can comprise In straight or branched part.Straight or branched low carbon chain alkenyl group is the most feasible and connects on any available position Connect, to provide stable compound.The example of low carbon chain alkenyl group includes vinyl, acrylic, isopropenyl, cyclobutenyl etc..
" low-carbon (LC) alkynyl ", alone or in combination, refers to containing 2-6 carbon atom (unless limited otherwise), comprises at least 1 Straight or branched hydrocarbon individual, preferably 1 triple carbon-carbon bonds.Straight or branched hydrocarbon low-carbon (LC) alkynyl group be the most feasible and Connect on any available position, to provide stable compound.The example of alkynyl group includes acetenyl, propinyl, butynyl Deng." cycloalkyl " refers to saturated or unsaturated non-aromatic monocyclic, bicyclo-or three ring carbocyclic ring system, and it is individual, also that every ring has 3-10 Can be 3-8, more preferably 3-6 annular atoms, such as cyclopropyl, cyclopenta, cyclohexyl, adamantyl (adamantyl) Deng.
" Heterocyclylalkyl " refers to have the saturated of 5 to 10 atoms or unsaturated non-aromatic ring alkyl, 1 to 3 in its medium ring Individual atom is replaced by hetero atom O, S or N, and optionally heteroaryl-condensed with benzene or 5-6 ring.Heterocyclylalkyl is also intended to bag Include S or N of oxidation, such as sulfinyl, sulfonyl and the N-oxide of tertiary ring nitrogen (tertiaty ring nitrogen).Heterocycle Alkyl is also intended to include such compound, and its medium ring carbon can be that oxygen is substituted, i.e. ring carbon is carbonyl, such as lactone and interior acyl Amine.The junction point of heterocycloalkyl ring is at carbon atom or nitrogen-atoms, to keep stable ring.The example of Heterocyclylalkyl include but not It is limited to morpholinyl, tetrahydrofuran base, dihydropyridine base, piperidyl, pyrrolidinyl, pyrrolidone-base, piperazinyl, dihydrobenzo furan Mutter base and indolinyl.
" cycloalkyl amino " represents group-NRaRb, wherein RaAnd RbIt is jointly formed 5-7 unit Heterocyclylalkyl with nitrogen, the most miscellaneous Cycloalkyl can comprise other hetero atom in ring, such as O, N or S, and can also be further by one or more low-carbon alkyls Replace.The example of 5-7 unit Heterocyclylalkyl includes but not limited to piperidines, piperazine, 4-methyl piperazine, morpholine and thiomorpholine.Should Understanding, when cycloalkyl amino is the substituent group in other parts, these are the most feasible and at any available atom Upper connection is to provide stable compound.
As used herein, " blocking group " refers to atomic cluster, and it is sheltered when the reactive group being connected in molecule, subtracts Little or hinder reactivity.The example of blocking group can be at T.W.Greene and P.G.Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed.2006), Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992) and Harrison and Harrison etc., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols.1-8 (John Wiley and Sons.1971-1996) finds.Representational amido protecting group includes formyl, second Acyl group, trifluoroacetyl group, benzyl, benzyloxycarbonyl group (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-tri- Methyl silicane base-ethylsulfonyl (SES), trityl and substituted trityl group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl Carbonyl (FMOC), nitro-Rhizoma et radix veratri (Radix Rhizoma Veratri) carbonyl (nitro-veratryloxycarbonyl) (NVOC), triisopropylsilyl (TIPS), benzenesulfonyl etc. are (referring also to Boyle, A.L. (editor), CURRENT PROTOCOLS IN NUCLEIC AClD CHEMISTRY, John Wiley and Sons, New York, Volume 1,2000).
As used herein, " leaving group " has in synthetic organic chemistry the meaning the most relevant with it, i.e. can be by The substituted atom of nucleophile or group, and include halogen (such as chloro, bromo and iodo), alkane sulfonyl oxy, aromatic hydrocarbons sulphonyl Epoxide, alkyl carbonyl oxy (such as acetate), aryl-carbonyl oxygen, mesyloxy, tosyloxy, fluoroform sulphonyl oxygen Base, aryloxy group (such as 2,4-dinitrophenoxy), methoxyl group, N, O-dimethyl hydroxylamino etc..
As used herein, " in treatment " " therapy " " multiple therapy " and similar terms " treated " in term, refers to effectively Amount uses material (any one or more of compound the most described herein), with prevention, alleviates or improve disease or disease The survival of object in one or more symptoms, i.e. indication, and/or extended treatment.
As used herein, term " disease that Fms and/or Kit is protein kinase mediated or disease " refer to such disease or Disease, wherein Fms protein kinase, Kit protein kinase or the biological function both Fms and Kit protein kinase affect disease or disease The development of disease, process and/or symptom, and/or the wherein regulation change disease of Fms and/or Kit protein kinase or sending out of disease Exhibition, process and/or symptom, described Fms protein kinase includes that its any sudden change, described Kit protein kinase include its any sudden change, Described both Fms and Kit protein kinases include its any sudden change.Disease that Fms and/or Kit is protein kinase mediated or disease bag Include and be adjusted to it treatment disease of benefit or disease be provided, wherein with Fms and/or Kit kinases inhibitor (a kind of or Multiple) treatment, give and suffer from the disease or disease or be in the object of disease or disease risk and provide treatment benefit, described Fms and/ Or Kit kinases inhibitor includes one or more compounds described herein.
As used herein, term " disease that Fms is protein kinase mediated or disease ", " disease of c-fms mediation or disease " And similar terms refers to such disease or disease, wherein the biological function of Fms protein kinase affects sending out of disease or disease Exhibition, process and/or symptom, and/or wherein regulating of Fms protein kinase changes disease or the development of disease, process and/or disease Shape, described Fms protein kinase includes its any sudden change.Disease or disease that Fms is protein kinase mediated include that Fms suppression provides The disease for the treatment of benefit or disease, wherein (a kind of with the Fms inhibitor including one or more compounds described herein Or multiple) treatment give and suffer from the disease or disease or be in the object of disease or disease risk and provide treatment benefit.
As used herein, term " disease that Kit is protein kinase mediated or disease ", " disease of c-Kit mediation or disease " And similar terms refers to a kind of disease or disease, wherein the biological function of Kit protein kinase affect disease or the development of disease, Process and/or symptom, and/or wherein regulating of Kit protein kinase changes disease or the development of disease, process and/or symptom, institute State Kit protein kinase and include its any sudden change.Disease or disease that Kit is protein kinase mediated include that Kit suppression provides treatment The disease of benefit or disease, wherein (a kind of or many with the Kit inhibitor including one or more compounds described herein Kind) treatment give and suffer from the disease or disease or be in the object of disease or disease risk and provide treatment benefit.
As used herein, term " dual Fms/Kit inhibitor " refers to suppress the compound of Fms and Kit protein kinase, i.e. has Just like in generally acknowledged Fms Kinase activity assays measure less than 500nM, less than 100nM, less than 50nM, less than 20nM, be less than 10nM, less than 5nM or less than the IC of 1nM50And have such as being less than of measuring in suitable generally acknowledged Kit Kinase activity assays 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50Compound, wherein Activity is to each Approximate Equivalent.If the IC of Kit kinase activity50IC divided by Fms kinase activity50Ratio 20 to 0.05, Also have 10 to 0.1, also have in the range of 5 to 0.2, it is believed that compound is Approximate Equivalent.This compounds is Fms egg in treatment It is effective in protein kinase mediated arbitrary of the most kinase mediated and Kit or both diseases or disease.Preferably, but unnecessary Ground, this compounds is selective relative to other protein kinase, and i.e. when comparing with another protein kinase, other is kinase whose IC50Divided by the kinase whose IC of Fms50＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100.Preferably, compound is selective relative to other protein kinase, other protein kinase include but not limited to CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.While it should be appreciated that dual Fms/Kit inhibitor can be used for treating any Disease that Fms is protein kinase mediated or disease, but the double inhibition of Fms and Kit acts in some disease for the treatment of or disease Thering is provided beneficial effect, described disease or disease include but not limited to metastatic breast cancer, carcinoma of prostate, multiple myeloma, black Melanoma, acute myeloid leukemia, brain metastes, neurofibroma, gastrointestinal stromal tumor, rheumatoid arthritis or multiple Sclerosis.
As used herein, term " dual Fms/Flt-3 inhibitor " refers to suppress the compound of Fms and Flt-3 protein kinase, I.e. have as generally acknowledged Fms Kinase activity assays measures less than 500nM, less than 100nM, less than 50nM, less than 20nM, little In 10nM, less than 5nM or less than the IC of 1nM50And have such as being less than of measuring in suitable generally acknowledged Flt-3 Kinase activity assays 500nM, less than 100nM, less than 50nM, less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50Compound, wherein Activity is to each Approximate Equivalent.If the IC of Flt-3 kinase activity50IC divided by Fms kinase activity50Ratio 20 to 0.05, also have 10 to 0.1, also have in the range of 5 to 0.2, it is believed that compound is Approximate Equivalent.This compounds in treatment is It is effective in arbitrary or both disease that Fms is protein kinase mediated and Flt-3 is protein kinase mediated or disease.Preferably, But unnecessarily, this compounds is selective relative to other protein kinase, i.e. when comparing with another protein kinase, its Its kinase whose IC50Divided by the kinase whose IC of Fms50＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100.Preferably, compound is selective relative to other protein kinase, other protein kinase described include but It is not limited to CSK, insulin receptor kinase, AMPK, PDGFR or VEGFR.While it should be appreciated that dual Fms/Flt-3 inhibitor can For treating disease protein kinase mediated for any Fms or disease, but the double inhibition of Fms and Flt-3 acts on treats certain Thering is provided beneficial effect in a little diseases or disease, described disease or disease include but not limited to acute myeloid leukemia.
As used herein, term " Fms selective depressant " refers to suppress Fms kinase whoseization relative to Kit Kinase Selectivity Compound, i.e. have as in generally acknowledged Fms Kinase activity assays measure less than 500nM, less than 100nM, less than 50nM, be less than 20nM, less than 10nM, less than 5nM or less than the IC of 1nM50And when measuring in suitable generally acknowledged Kit Kinase activity assays To there is the Kit kinases of ＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100 IC50Divided by the kinase whose IC of Fms50The compound of ratio.This compounds is in disease protein kinase mediated for treatment Fms or disease It is effective on disease, and does not affects (effecting) Kit protein kinase.Preferably, but unnecessarily, this compounds is relative It is selective in other protein kinase, i.e. when comparing with another protein kinase, other kinase whose IC50Kinase whose divided by Fms IC50＞ 20, also ＞ 30, also ＞ 40, also ＞ 50, also ＞ 60, also ＞ 70, also ＞ 80, also ＞ 90, also ＞ 100.Preferably, chemical combination Thing is selective relative to other protein kinase, and other protein kinase described includes but not limited to that CSK, Insulin receptor INSR swash Enzyme, AMPK, PDGFR or VEGFR.It is situated between while it should be appreciated that Fms selective depressant can be used for treating any Fms protein kinase The disease led or disease, but Fms selectivity is treating offer beneficial effect, described disease or disease in some disease or disease Include but not limited to rheumatoid arthritis, Alzheimer, parkinson, osteoarthritis, nephritis, diabetic nephropathy or Renal hypertrophy.
As used herein, term " blood brain barrier " refers to prevent many materials, including some little molecule medicine in blood circulation Thing, enters the physical barriers of central nervous system (CNS).The medicine being intended to interact with the molecular targets in CNS must be worn More blood brain barrier is to arrive their target.On the contrary, peripheral action agent (peripherally acting agent) should not This passes through blood brain barrier to be avoided side effect relevant for any CNS.The ability of compound penetration blood brain barrier is oozed with blood brain barrier The ratio of property or the compound Css in brain and in blood represents thoroughly.Experimental blood brain barrier permeability can be by internal Method is measured.Various method can be used to measure the part of the compound from blood transportation to cerebral tissue, join including brain blood system The perfusion of (brain blood partitioning), brain, brain uptake index (brain uptake index) and brain microdialysis (intracerebral microdialysis).But, these vivo approaches are substantially laborious and underproductivity. It practice, computational methods (in silico computational methods) are frequently utilized for confirming in vivo it in silicon Front prediction blood brain barrier permeability.Up to the present the most of blood brain barrier models having been built up are based on most compounds The hypothesis of blood brain barrier is passed through by Passive diffusion conveying.In all physics chemistry character, polar surfaces amasss (polar Surface area) (PSA) show the dependency best with the blood brain barrier permeability of Passive diffusion compound.Experimental evidence Show there is the long-pending compound of 100 or bigger polar surfaces and typically have and low pass through blood brain barrier probability.Use disclosed calculation Method (Ertl etc., J.Med.Chem.2000,43:3714-3717) is readily calculated polar surfaces by compound structure and amasss.Although It is to be understood that Fms selective depressant can be used for treating disease protein kinase mediated for any Fms or disease, but effectively wears The more compound of blood brain barrier provides beneficial effect in some disease or disease treating, described disease or disease include but not It is limited to multiple sclerosis, glioblastoma multiforme, Alzheimer and parkinson, and not operatively passes through blood brain screen The compound of barrier provides beneficial effect in some disease for the treatment of or disease, and described disease or disease include but not limited to class wind Wet arthritis, osteoarthritis, atherosclerosis, systemic lupus erythematosus (sle), glomerulonephritis, interstitial nephritis, systemic lupus erythematosus kidney Inflammation, renal tubular necrosis, diabetic nephropathy or renal hypertrophy.
As used herein, term " solid form " refer to pharmaceutically active compound solid preparation (i.e. neither gaseous state also It is not the preparation of liquid), it is suitable to bestow to intended animal target, for therapeutic purposes.Solid form includes any compound Thing, such as salt, eutectic or unbodied complex and any polymorph of compound.Solid form can be substantially crystallization , hemicrystalline or be substantially unbodied.Solid form can directly be used or have the conjunction improving pharmaceutical properties for preparation Suitable compositions.Such as, during solid form can be used on the preparation comprising at least one pharmaceutically acceptable carrier or excipient.
As used herein, term " substantially crystallization " material comprises and has the material more than about 90% degree of crystallinity, and " knot Brilliant " material includes having the material more than about 98% degree of crystallinity.
As used herein, term " essentially amorphous " material includes the material that degree of crystallinity is not more than about 10%, and " nothing Setting " material include degree of crystallinity be not more than about 2% material.
As used herein, term " hypocrystalline " material includes more than 10% degree of crystallinity but the material of no more than 90% degree of crystallinity Material, preferably " hypocrystalline " material include more than 20% degree of crystallinity but the material of no more than 80% degree of crystallinity.In the present invention one In aspect, the mixture of the solid form of compound can be prepared, the most amorphous and mixture of crystalline solid forms, such as with " hypocrystalline " solid form is provided.This " hypocrystalline " solid form can be prepared by methods known in the art, such as, passes through Amorphous solid and crystalline solid forms are mixed with desired ratio and prepares.In some cases, mix with acid or alkali The compound closed forms amorphous complex；Semi-crystalline solid is available exceedes compound and sour or alkali in amorphous complex The amount of stoichiometric compound component prepare, thus producing, excess compounds stoichiometric based on it is crystalline The a certain amount of amorphous complex of formula.The amount of the compound of the excess used in the preparation of complex can be adjusted, to produce Raw solid form mixture provides the desired ratio of amorphous complex and crystalline compounds.Such as, in sour or alkali and change In the case of the amorphous complex of compound has 1: 1 stoichiometry, it is that 2: 1 mol ratio preparations are described with compound and acid or alkali Complex will produce 50% amorphous complex and the solid form of 50% crystalline compounds.Such as, by offer, there is improvement Bio-pharmaceutical character and the amorphous component of crystallographic component, the mixture of this solid form can be useful as medicine 's.Amorphous component is by easier biological utilisation, and crystallographic component has the bioavailability of delay.This mixture can provide Quickly and extend be exposed to reactive compound.
As used herein, term " complex " refers to pharmaceutically active compound and the combination of other molecular species, its shape Become or produce the new chemical species of solid form.In some cases, complex can be salt, the most other molecular species Class provides the acid/base counter ion counterionsl gegenions of the acid/base group of compound, results in the acid of usual salt: alkali interacts.Although it is this kind of Salt form typically basic crystallization, but they can also is that partially crystallizable, essentially amorphous or unbodied form. This other molecular species combines pharmaceutically active compound and defines non-salt eutectic, i.e. compound and molecular species in some cases Class is not by typical acid: interacts by the way of alkali interaction, but still forms basic crystalline texture.Eutectic also can be by Compound and the salt formation of other molecular species.In some cases, complex is essentially amorphous complex, and it can contain It is formed without the salt acid of typical case's salt crystal: alkali interacts, but forms essentially amorphous solid, i.e. its X-ray powder diffraction Spectrogram does not show the solid of spike (such as showing amorphous diffraction corona (halo)).
As used herein, term " stoichiometry " refer to combine formed complex two or more reactant mole Ratio, the such as mol ratio of the compound of acid or alkali and the amorphous complex of formation.Such as, acid or alkali mix with the 1: 1 of compound Thing (i.e. every mole compound 1 equimolar acid or alkali) produces has 1: 1 stoichiometric amorphous solid.
As used herein, term " compositions " refers to the medicine system being suitable to use to reach therapeutic purposes to intended object Agent, it contains at least one pharmaceutically active compound, including its any solid form.Said composition can include at least one medicine Acceptable component, such as carrier or excipient on, to provide the improvement preparation of compound.
As used herein, term " object " refers to the living organism with compounds for treating described herein, includes but not limited to appoint What mammal, the such as mankind, other primates, sport animals, commercial object animal such as cattle, farm-animals such as horse or House pet such as Canis familiaris L. and cat.
As used herein, term " bio-pharmaceutical character " refers to that the compound of the present invention or the pharmacokinetics of complex are made With, including using the dissolving of rear compound to animal target, absorbing and be distributed.Therefore, some solid of the compound of the present invention The amorphous complex of the compound of form, the such as present invention, it is intended to provide the dissolving of the improvement of reactive compound and absorption, its Generally it is reflected as the C improvedmax(maximum that i.e. concentration in blood plasma reaches after using medicine) and the AUC improved (are i.e. executing Area with below the curve to the time of the drug plasma concentration after medicine).
Term " pharmaceutically acceptable " represents that indication material does not have the quality that in view of by treated Disease or disease and respective route of administration, this character uses this thing by making the most careful medical practitioner avoid to patient Matter.Such as, for injection, usually require that such material is the most aseptic.
Some compound of the present invention can exist with non-solvate form and solvate forms, including hydration shape Formula." hydrate " refers to the complex formed by hydrone with solute molecule or ions binding." solvate " refers to pass through solvent The complex that molecule is formed with solute molecule or ions binding.Solvent can be organic compound, inorganic compound or the two In conjunction with.Solvate means to include hydrate.Some examples of solvent include but not limited to methanol, DMF, Oxolane, dimethyl sulfoxide and water.Normally, solvate forms is equivalent to non-solvate form and is included in this In the range of invention.Some compound of the present invention can exist with polycrystalline or amorphous form.Generally, all physical form The purposes considered for the present invention is equivalence and is intended within the scope of the invention.
In the present context, term " treatment is effective " or " effective dose " represent that the amount of described material and material is in advance Prevent, alleviate or improve one or more symptoms of disease or disease, and/or extend that to connect the survival of subject object be effective 's.
In the present context, term " collaborative effective " or " synergism " refer to upper the most effective two kinds or many for the treatment of Plant compound, when used in combination, it is provided that bigger than the addition effect desired by effect based on every kind of use compound self The therapeutic effect of improvement.
" measure " collection of data of establishment and the concrete outcome about experiment condition referring to experiment condition.Such as, According to enzyme to can the ability of detection substrate effect, enzyme can be measured.According to compound and certain target molecules or multiple target molecule In conjunction with ability, compound can be measured.
As used herein, term " regulation (modulating) " or " adjusting (modulate) " refer to change biologic activity, The effect of especially relevant to specific biological molecules such as protein kinase biologic activity.Such as, by reducing biomolecule Such as the activity of enzyme, the inhibitor of specific biological molecules regulates the activity of this biomolecule such as enzyme.This activity typically basis The compound of the inhibitor inhibition concentration (IC to such as enzyme50) represent.
As regulator or possibly as in the use of compound of regulator, the context that detects or screen, term " contact " expression and make described compound (one or more) and specific molecular, complex, cell, tissue, biology or other appointment Material is sufficiently close together so that potential binding interactions and/or change can occur between this compounds and other designated substance Learn reaction.
" pain " or " antalgesic " can be acute and/or chronic pain, includes but not limited to arachnoiditis；Arthritis (such as osteoarthritis, rheumatoid arthritis, mandatory spondylitis, gout)；(such as sciatica, intervertebral disc are broken in backache Split, spondylolisthesis, radiculopathy)；Burn pain；Cancer pain；Dysmenorrhea；Headache (such as migraine, cluster headache (cluster Headache), tension headache)；Head and face ache (such as cranial neuralgia, trigeminal neuralgia)；Hyperpathia；Hyperpathia (hyperpathia)；Inflammatory pain is (such as with irritable bowel syndrome, inflammatory bowel, ulcerative colitis, Crohn disease, wing Pain that Guang inflammation is relevant, the pain infected from antibacterial, fungus or virus)；Keloid or scar tissue are formed；Work or divide Childbirth pain；Myalgia (such as polymyositis, dermatomyositis, occlusion body myositis, repeatability stress injury (such as writers spasm, canalis carpi Syndrome, tendinitis, tenosynovitis) cause)；Myofasical pain syndrome (such as fibromyalgia)；Neuropathic pain (such as glycosuria Sick neuropathy, skin scorch pain, entrapment neuropathy, brachial plexus this de-wound, occipital neuralgia, gout, sympathetic reflex The god that malnutrition syndrome, phantom limb or amputation postoperative pain, postherpetic neuralgia, central pain syndrome or wound cause Through pain (such as nerve injury), disease (such as diabetes, multiple sclerosis, guillain-Barre syndrome, myasthenia gravis, god (such as parkinson disease, Alzheimer, amyotrophic lateral sclerosis or cancer treatment) is become through sexually transmitted disease (STD)；The pain relevant to dermatosis Bitterly (such as herpes zoster (shingles), herpes simplex, cutaneous tumor, cyst, neurofibromatosis)；Athletic injury is (such as Incised wound, sprain, pull, abrade, dislocate, rupture, spinal cord (spinal chord), head)；Spinal canal stenosis；Surgical pain； Tactile allodynia；(such as vasculitis, coronary artery disease, reperfusion injury are (such as to nibble jaw arthrosis, angiopathy or damage Ischemia, apoplexy or myocardial infarction subsequently))；Other concrete organ or tissue's pain (such as ophthalmalgia, keratalgia, osteodynia, heart Bitterly, Encelialgia (such as kidney, gallbladder, the intestines and stomach), arthralgia, have a toothache, pelvic hypersensitivity, pelycalgia, renal colic, urinary incontinence)；Other Disease (such as sicklemia, AIDS, herpes zoster (herpes zoster), psoriasis, the uterus relevant to pain Endometriosis, asthma, chronic obstructive pulmonary disease (COPD), pneumosilicosis, pulmonary sarcoidosis, esophagitis, heartburn, gastroesophageal reflux disease, Gastric duodenal ulcer, functional dyspepsia, bone resorption diseases, osteoporosis, brain malaria, bacillary meninges Scorching)；Or owing to graft-versus-host repels or the pain that causes of allograft rejection.
Kinases target and indication
Protein kinase plays a crucial role in terms of propagating biochemical signals in various biological approaches.Described 500 kinds with On kinases, and specificity kinase has been directed to disease or the disease (that is, indication) of wide scope, and it such as includes without It is limited to cancer, cardiovascular disease, inflammatory diseases, neuropathy and Other diseases.Equally, kinases represents what small molecule therapy was interfered Important control point.The specific target protein kinases that the present invention considers, i.e. Fms kinases and Kit kinases be described in the art, its Include but not limited to described in U.S. Patent Application Serial Number 11/473,347 (see also PCT Publication WO2007002433) , about this kind of kinase target and following, the disclosure of which is incorporated herein by reference:
Fms: target kinase Fms (i.e. cat MacDonough sarcoma) is initially from Susan's MacDonough bacterial strain of cat sarcoma virus A member of isolated gene family.Fms is that the transmembrane tyrosine of the 108.0kDa encoded by chromosome 5q33.2-q33.3 swashs Enzyme (symbol: CSF1R).The structure of transmembrane receptor Fms includes two Ig spline structure territories, IgC2 spline structure territory, two other Ig Spline structure territory, TM domain and TK domain.
Fms is the receptor of M-CSF (M-CSF), and for Monocyte-macrophages pedigree Growth and break up most important.After M-CSF is bound to the extracellular domain of Fms, Receptor dimerization and trans Autophosphorylation cytoplasmic tyrosine residues.
The M-CSF initially described by Robinson and partner (Blood.1969,33:396-9) is to control macrophage The cytokine of generation, differentiation and function.M-CSF stimulates CFU-GM to the differentiation of mature monocyte, and it is thin to extend monokaryon The survival of born of the same parents.And, M-CSF strengthen the cytotoxicity in mononuclear cell and macrophage, peroxide generation, phagocytosis, The secondary cell factor of chemotaxis and other factors produces.The example of this other factors includes granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6) and interleukin 8 (IL-8).M-CSF stimulates hemopoietic, promotes that broken bone is thin The differentiation of born of the same parents' CFU-GM and propagation and there is on lipid metabolism far-reaching effect.And, M-CSF is important in gestation. Physiologically, substantial amounts of M-CSF results from Placenta Hominis, and believe trophoderm differentiation on play Essential Action (Motoyoshi, Int J Hematol.1998,67:109-22).The high serum M-CSF level of early pregnancy may participate in immunity Mechanism, it is responsible for the maintenance (Flanagan&Lader, Curr Opin Hematol.1998,5:181-5) of gestation.
The unconventionality expression of Fms and/or activation have been directed to acute myeloid leukemia, AML (Ridge etc., Proc.Nat.Acad.Sci., 1990,87:1377-1380).Believe the non-part by receptor of the sudden change on codon 301 Dependency and structure tyrosine kinase activity guide tumor to convert.The tyrosine residue having been shown on codon 969 relates to Negative regulation activity, it is interrupted by aminoacid replacement.Therefore, Fms suddenlys change in chronic myelomonocytic leukemia and AML type Being most common (20%) in M4 (23%), the feature of the two is mononuclear cell differentiation.
The disease relating to AML is chronic granulocytic leukemia (CML).Bone marrow blasts crisis (BC) process at CML In, other chromosomal abnormality nonrandom occurs in more than the patient of 80%.But, it has been reported that these cytogenetics changes Clinical symptom some months prior to CML-BC was to several years, and this implies that other biological activity may participate in the multi-step mistake in the CML sudden turn of events Cheng Zhong.Have shown that the autocrine of somatomedin produces to occur in AML especially at several hematologic malignancies.Specchia etc. [Br J Haematol.1992Mar；80 (3): 310-6] IL-1 β gene is had turned out in nearly all bone marrow blasts crisis In CML in the case of be expressed, and a high proportion of situation shows the structure representation of M-CSF gene.At Specchia etc. Many same patient in research show co expression while Fms.Expose to phorbol myristate second leukaemia After acid esters (PMA), three in five patients of research demonstrate the release of M-CSF protein；But, these patients In be not detected by significant interleukin 3 (IL-3), granulocyte-macrophage colony stimutaing factor (GM-CSF) or grain Colony-stimulating factor (G-CSF).This shows that the secretory different mode of somatomedin is present in AML and CML, and Different molecule activities may relate to the control of leukemia propagation.
The observation that the generation of the main macrophage growth factor of M-CSF increases in the tissue during inflammation (Le Meur etc., J.Leukocyte Biology.2002；72:530-537) provide the effect of Fms in some disease.Example As, COPD is characterized as the air-flow of completely reversibility limiting.Air-flow limit be typically the most positive and with lung to deleterious particle or The abnormal inflammatory response of gas is relevant.By air flue, parenchyma and pulmonary vasculature, observe the chronic inflammatory disease of COPD.Inflammation Cell mass is made up of together with the eosinocyte in some patients neutrophilic leukocyte, macrophage and T lymphocyte.Require huge biting Cell by release medium such as TNF-a, IL-8 and LTB4 play in COPD inflammation coordinate combination effect, medium such as TNF-a, IL-8 and LTB4 can destroy lung structure and/or maintain neutrophilia inflammation.
Further, the conduction of M-CSF/fms signal is to closing weight to the survival of osteoclast formation and osteoclast precursor Want.Such as, in menopause, the estrogen of loss causes the M-CSF increased and thus increases amount of osteoclast and bone suction Receiving, it causes risk of bone fracture to increase and osteoporosis.Therefore, the blocking-up of this signal is the purpose of suppression bone resorption (Teitelbaum, Science.2000；289:1504:Rohan, Science.2000；289:1508).
A kind of inflammatory diseases of atherosclerotic vessels wall is relevant with significant M & M.Dynamic Fms inhibition in the treatment and prevention of pulse atherosclerosis depends on several observation (Libby, Nature.2002；420: 868-874).Firstly, there are the mononuclear cell in endarterium and add the expression removing receptor the lipoprotein making degeneration Internalization.The macrophage of the load lipid obtained develops into the foam cell feature of atherosclerotic lesion.Sebaceous cyst secretion is thin Macrophage in intracellular cytokine and somatomedin relates to infringement process.It addition, macrophage replicates in inner membrance.By Fms, M- CSF activated monocyte extremely loads the conversion of the macrophage of lipid and amplifies the expression removing receptor A.It is true that tremulous pulse is hard Dissipating rashes block overexpression M-CSF vital for atherosclerotic process.Have been found that the mice lacking M-CSF is than tool Have normal M-CSF the mice less serious atherosclerosis of experience (Rajavashisth, etc., J.Clin.Invest.1998；101:2702-2710；Qiao, etc., Am.J.Path.1997；150:1687-1699).Therefore, The inhibitor of Fms has interrupted the conduction of M-CSF signal, and harm mononuclear cell is deposited to macrophage foam cell process, macrophage Live and replicate and the cytokine signaling conduction of participation infringement process.
In emphysema the effect of M-CSF and Fms show relate to by control matrix metalloprotease regulation elastin laminin metabolism. M-CSF to regulate internal pulmonary alveolar macrophage (AM) accumulation and function work (Shibata etc., Blood 2001,98: pp.2845-2852).The mice of osteosclerosis (Op/Op) do not have detectable go out M-CSF and show macrophage quantity Variable tissue specificity reduces.Therefore, quantity is reduced and owing to the shortage of M-CSF has in Op/Op mice by conjecture AM The function changed.Shibata etc. find, compare with the discovery in the littermate control of age-matched, the lung that pulmonary determines in dividing Macrophage quantity in 20 the biggest Op/Op mices reduces, but does not reduce in the Op/Op mice more than 4 months.With Comparing, the AM quantity recovered by bronchoalveolar lavage (BAL) in Op/Op mice that is young rather than that grow up also drops Low.Importantly, the AM of Op/Op mice spontaneously discharges higher levels of matrix metalloproteinase (MMP) than the AM of comparison.With increasing The MMP release added is consistent, and Op/Op mice has abnormal elastin deposition and do not deposits at molecule or the cell sign of pneumonia The most spontaneously develop into emphysema.Therefore, by the activity of metalloelastase in M-CSF regulation macrophage Lung or the degraded of blood vessel elastase fiber can be controlled.
Include that M-CSF, metastatic carcinoma cell cause owing to producing osteoclast occurrence factor by tumor cell The bone destruction relevant with fracture, pain, deformation and hypercalcemia (Clohisy etc., Clin.Orthop.2000,373: 104-14).M-CSF be bound to Fms product stimulate the formation of osteoclast and bone resorption activity (Kodama etc., J.Exp.Med.1991,173:269-72；Feng etc., Endocrinology 2002,143；4868-74).Therefore, at Fms water The suppression of flat lower osteoclast activity provides the competitive target improving Bone tumour.Fms is also to improve transitivity mammary gland Target (Lawicki etc., Clin Chim Acta.2006, Sep, 371 (1-2): the 112-6 of cancer；Wyckoff etc., Cancer Res.2007, Mar 15,67 (6): 2649-56).
Nephritis is the inflammation of kidney.It may such as be infected by the antibacterial of kidney or exposure to toxin causes.But, nephritis is more general Developed by abnormal immunoreation everywhere, such as when antibody is attacked kidney itself or is attached to the antigen of nephrocyte, or work as During the cell that the antigen-antibody complex that other places are formed in vivo is attached in kidney, abnormal immunoreation can occur.Some classes The nephritis of type relates to being filtered by the nephridial tissue of leukocyte and the deposition of antibody.In other type of nephritis, the whitest thin In the case of born of the same parents or antibody, inflammation can be made up of swollen tissue or scarring.And, nephritis can occur in any position of kidney. About glomerule, cause urine to produce decline the gradually destruction of glomerule and metabolic waste product accumulates in blood.When right When the destruction of glomerule is serious, inflammatory cell and the accumulation of impaired messangial cell, oppress the capillary tube in glomerule and hamper Hinder filtration.Scarring can develop, and weakens renal function and reduces the generation of urine.In some cases, microthrombus can be in thin vessels Formed, reduce renal function further.The most typically, nephritis relates to tubulo-interstital tissue；This inflammation is referred to as Tubulointerstitial Nephritis.When inflammation damages tubule and tubulo-interstital tissue, kidney may become can not concentrate urine, can not discharge (excretion) from health Metabolic waste product or balance sodium and the excretion of other electrolyte such as potassium.When tubule and tubulo-interstital tissue are destroyed, renal failure Exhaust and usually develop.Accordingly, because include the regulation of the inflammatory response of disease aetiology, the suppression of Fms provides in nephritis and treats The target interfered.
It is the common disease with poor prognosis that lupus nephritis i.e. kidney relates to systemic lupus erythematosus (sle) (SLE) Performance.Experimental data supports the immunopathogenesis of the potential overlap of at least three of lupus nephritis.First, mainly by DNA and The circulating immune complex of anti-DNA composition deposits in kidney.The complement activation obtained and the chemotaxis of neutrophilic leukocyte cause Local inflammation process.Secondly, being formed in situ of antigen and antibody complex can again result in complement activation and leukocyte mediation Damage.3rd, the antibody of opposing specific cell target can cause injury of kidney.The SLE patient with anti-phospholipid antibody syndrome In observe other mechanism.Glomerule thrombosis can be caused by hypercoagulability, and hypercoagulability supports with guiding Antibody (such as biological false positive VDRL, anticardiolipin antibody and the lupus anticoagulant of anti-electronegative phospholipid-protein complex Thing).Mesentery lupus nephritis find with normal diagnosis or have moderate albuminuria but be generally not present hypertension or Abnormal urinary sediment.It is usually relevant with the worst prognosis of the survival of kidney that focal and diffusivity breeds LGN And can be with the nephrotic syndrome, serious hypertension and the urinary sediment of exception.In the case of there is not hypertension, membranous type wolf Skin ulcer nephritis has been usually present albuminuria, moderate to height but generally normal urinary sediment.Mesentery Lupus nephritis is generally with good Prognosis relevant, but Hypertrophic Lupus nephritis, particularly diffusivity variant, be generally characterized as hypertension, red cell cast and The severe exacerbation of renal function.The nephrotic syndrome in the case of there is not hypertension, actively urinary sediment or significantly complement minimizing The membranous type variant of disease display Lupus nephritis.Membranous type nephropathy is generally correlated with to the relevant holding of good prognosis and renal function. But, in the presence of the albuminuria of lasting nephrotic scope, membranous type Lupus nephritis in fact may result in renal failure and evening Phase nephropathy (ESRD).Accordingly, because regulation comprises the inflammatory response of disease aetiology, the suppression of Fms provides to be controlled in lupus Treat the target interfered.
In the glomerulonephritis of many forms, macrophage accumulation is prominent feature.The local of macrophage in kidney Propagation has been described in the glomerulonephritis of the mankind and experiment and can play a significant role to strengthening inflammatory response. Isbel etc. (Nephrol Dial Transplant 2001,16:1638-1647) have investigated local macrophage propagation and M- Relation between the kidney expression of CSF.Find that the M-CSF of bead and tubulo-interstital expresses in mankind's glomerulonephritis to be adjusted by forward Joint, the most prominent in the proliferative form of disease.Because this has relation with local macrophage propagation, show at mankind's glomerulonephritis The kidney M-CSF increased in inflammation produces and plays a significant role in regulation local macrophage propagation.(UUO-in the pattern of nephritis The obstruction of Induced by Unilateral Ureteral Obstruction), anti-Fms Antybody therapy decreases macrophage accumulation (Le Meur etc., J Leukocyte Biology, 2002,72:530-537).Therefore, in glomerulonephritis, the suppression of Fms provides the target that treatment is interfered.
Insulin resistance and obesity are the features of type ii diabetes, and gather at insulin resistance and abdomen interior fat Between there is strong connection (Bjorntrop, Diabetes Metab.Res.Rev., 1999,15:427-441).Current card It was noted that the macrophage of fatty tissue inner accumulated discharges TNF-a and causes adipose cell to change (mastocytosis, steatolysis Effect, the insulin sensitivity reduced) other factors and also promote the insulin resistance in surrounding tissue.Therefore, at II Macrophage accumulation in patients with type Ⅰ DM is important for progression of disease.Therefore, the suppression of Fms prevention insulin resistance and In the development of hyperglycemia, there are potentiality.
Similarly, in tissue, add the generation of the main macrophage growth factor of M-CSF during inflammation Observation point out that Fms is in disease such as the effect in inflammatory diseases.More specifically, because find elevated levels in morbid state The regulation of M-CSF, Fms activity can improve the disease relevant with the M-CSF of growth level.
Fms inhibitor can be used for treating inflammatory and autoimmunity indication, its include but not limited to rheumatoid arthritis, Osteoarthritis, arthritic psoriasis, psoriasis, dermatitis, mandatory spondylitis, polymyositis, dermatomyositis, systemic sclerosis, Idiopathic juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, polymyalgia rheumatica, sjogren's disease, langerhans' cells histiocytosis (LCH), this Base of a fruit Er Shi disease, inflammatory bowel disease syndrome, ulcerative colitis, Crohn disease, systemic lupus erythematosis (SLE), transplanting Rejection, chronic obstructive pulmonary disease (COPD), emphysema, river Ji Shi are sick, (macrophage activation is comprehensive for blood phagocytosis syndrome Disease), multicentric reticulohistiocytosis and atherosclerosis；Metabolic disease, its include but not limited to type i diabetes, Type ii diabetes, insulin resistance, hyperglycemia, obesity and lipolysis；Bone structure, mineralising and bone formation and the disease of absorption Disease, it includes but not limited to that the increase of osteoporosis, osteodystrophy, risk of bone fracture, Paget, hypercalcemia, infection are situated between The osteolysis that the osteolysis (such as myelitis) led and Periprosthetic or wear debris mediate；Kidney and genitourinary disorders, It includes but not limited to endometriosis, nephritis (such as glomerulonephritis, interstitial nephritis, lupus nephritis), renal tubules The renal complication (such as diabetic nephropathy) downright bad, diabetes are relevant and renal hypertrophy；Central nervous system disease, it includes But be not limited to multiple sclerosis, amyotrophic lateral sclerosis (ALS), myasthenia gravis, chronic Demyelinating Polyneuropathy, Other demyelination, apoplexy, Alzheimer and parkinson；Inflammatory and chronic pain, it includes but not limited to Osteodynia；Malignant tumor, it includes but not limited to multiple myeloma, acute myeloid leukemia (AML), chronic myeloid Leukemia (CML), pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, breast carcinoma, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, bone Giant cell tumor, the giant cell tumor (TGCT) of stndon sheath, pigmented villonodular synovitis (PVNS), tumor-blood-vessel growth, melanin Tumor, glioblastoma multiforme, glioma, central nervous system other onch-tumor metastasis to other tissue and its Its chronic myeloproliferative disease such as myelofibrosis；Vasculitis, it includes but not limited to the many tremulous pulsies of collagen vascular disease, nodositas Inflammation, Behcet's disease, sarcoidosis, familial Mediterranean fever, churg-Strauss vasculitis, temporal arteritis, giant cell arteritis, High iS-One arteritis；Adaptation of eye disease, it includes but not limited to the macula lutea that uveitis, scleritis, retinitis, age are relevant Degeneration, choroidal neovascularization, diabetic retinopathy；Genetic diseases, it includes but not limited to macrognathia, neurofibroma； Catch indication, and it includes but not limited to the infection relevant with human immunodeficiency virus, hepatitis B virus, the third type liver Scorching virus, Human granulocytic anaplasmosis；Lysosomal storage disorder, its include but not limited to familial splenic anemia, Fabry disease, Buddhist nun- Skin Er Shi is sick；Gastrointestinal indication, it includes but not limited to liver cirrhosis；Lung indication, it includes but not limited to pulmonary fibrosis, acute Injury of lung (such as air-conditioning causes, cigarette or toxin cause)；And operative indication, it includes but not limited to that (cardiopulmonary) shunt Art, vascular surgery and vascular graft.
Kit: target kinases Kit (i.e. cat Hardy-Zuckerman 4 sarcoma virus oncogene) is by chromosome 4q12 The 109.9kDa transmembrane tyrosine kinase (symbol: KIT) of coding.It is raw that receptor protein tyrosine kinase (RPTK) regulation controls cell Long and propagation key signal transductory cascade reacts.Stem cell factor (SCF) receptor Kit is type III cross-film RPTK, its bag Include five extracellular immunoglobulin (IG) domains, single membrane spaning domain and by the separate somatoblast of kinase insert Matter kinase domain.Kit plays important work in the growth of melanocyte, mastocytosis, germ and hematopoietic cell With.
Stem cell factor (SCF) is the protein encoded by SI locus, and based on the biology for confirming it Learn performance be also known as kit part (KL) and mast cell growth factor (MGF) (at Tsujimura, Pathol Int 1996, 46:933-938；Loveland etc., J.Endocrinol 1997,153:337-344；Vliagoftis etc., Clin Immunol 1997,100:435-440；Broudy, Blood 1997,90:1345-1364；Pignon, Hermatol Cell Ther 1997,39:114-116；And Lyman etc., Blood 1998,91:1101-1134 summarize).Abbreviation SCF herein refers to Kit part.
SCF is synthesized into the transmembrane protein with 220 or 248 Dalton molecular weights, and this depends on outside the coding of mRNA The optional montage of aobvious son 6.Bigger protein can be cut to solvable, the glycosylation of non-covalent dimerization by Proteolytic enzyme Protein.Solvable and film-combining form SCF can be bound to Kit and activate Kit.Such as, in skin, SCF mainly by Fibroblast, keratinocyte and epithelial cell are expressed, and melanocyte and the activity of mastocyte of Kit is expressed in this regulation. In bone, Expressing of Bone Marrow Stromal SCF also regulates the hemopoietic of Kit expressing stem cell.In the gastrointestinal tract, intestinal is upper Chrotoplast is expressed SCF and affects Ka Haer (Cajal) Interstitial cell and intraepithelial lymphocyte.In testis, Sai Tuoli is thin Born of the same parents and granulosa cell express SCF, and it is by the regulation spermatogenesis that interacts with Kit in sexual cell.
According to OMIM, it is requisite for conducting for internal and external primordial germ cell growth from the signal of Kit. Downstream effect of many KIT signal conducting paths is identified in other cell type, but how these molecules are controlled Primordial germ cell processed survival and propagation are unknown.For want of effective method is easily to manipulate the gene in these cells Expressing, the determination of the KIT effector worked in primordial germ cell has been subjected to hinder.De Miguel etc. (2002) lead to The effect of the gene transfer crossing test retrovirus-mediated method overcomes with the gene expression in manipulation Mammalian germ cells This problem.They find that primordial germ cell can be successfully by various types of retroviral infections.They use this side Method with prove control primordial germ cell growth on AKT1 important function (OMIM MIM Number:164920: 04/17/ 2006)。
The unconventionality expression of Kit and/or activation have been directed to various pathological state.Such as, Kit is pathological to neoplasia The evidence of contribution includes that it is with leukemia with mastocytoma, small cell lung cancer, carcinoma of testis and gastrointestinal tract and central nervous system The certain cancers of system is relevant.It addition, Kit has been directed in the female genital tract sarcoma of neuroectodermal origin and fine with nerve The dimension relevant schwann's tumor of tumor formed carcinogenic on play a role.Find that mastocyte relates to changing the microenvironment of tumor and strengthens tumor Growth (Yang etc., J Clin Invest.2003,112:1851-1861；Viskochil, J Clin Invest.2003, 112:1791-1793).Kit inhibitor can also be used for targeting melanoma (Smalley etc., Histol Histopathol.2009, May, 24 (5): 643-50), gastrointestinal stromal tumor (Demetri, GD, Semin Oncol.2001, Oct, 28 (5Suppl 17): 19-26), neurofibroma (Yang etc., Cell, 2008, Oct 31,135 (3): 437-48) and Multiple sclerosis (Secor etc., J Exp Med.2000, Mar 6,191 (5): 813-22).
Kit inhibitor can be used for treating malignant tumor, and it includes but not limited to that mastocytoma, small cell lung cancer, non-are little Cell lung cancer (NSCLC), carcinoma of testis, cancer of pancreas, breast carcinoma, Meike ear Schwann Cells cancer, female reproductive tract cancer, neuroderm rise The sarcoma in source, rectal cancer, cancer in situ, gastrointestinal stromal tumor (GIST), tumor-blood-vessel growth, glioblastoma multiforme, astroglia Glucagonoma, neuroblastoma, neurofibroma (including that the schwann's tumor relevant with neurofibroma is formed), acute myeloid Property leukemia, acute lymphatic leukemia, chronic lymphocytic leukemia, mastocytosis, melanoma and dog loose thin Born of the same parents' tumor；Cardiovascular disease, it includes but not limited to that atherosclerosis, cardiomyopathy, heart failure, pulmonary hypertension and lung are fine Dimensionization；Inflammatory and autoimmunity indication, it includes but not limited to, allergy, anaphylaxis, asthma, rheumatoid arthritis, allergy Property rhinitis, multiple sclerosis, inflammatory bowel disease syndrome, graft-rejection, hypereosinophilia, urticaria and skin Scorching；Gastrointestinal indication, it includes but not limited to gastroesophageal reflux disease (GERD), esophagitis and gastrointestinal ulceration；Adaptation of eye disease, It includes but not limited to uveitis and retinitis；And nervous system indication, it includes but not limited to migraine.
Flt3:Target kinase Flt3 (that is, Fms-sample tyrosine kinase 3) be the 112.8kDa that encoded by chromosome 13q12 across Film tyrosine kinase (symbol: FLT3).Isolate above according to (Genomics 1991,9:380-385) such as OMIM, Rosnet The newcomer of classification 3 receptor discussed.They prove to be referred to as other of this gene and this race of the family tyrosine kinase of FLT3 Member has the sequence similarity of strong row.Lymphohematopoietic stem cells is used as the storage of the most all hemocytees, but only makes up The mankind of about 0.01% or muroid medullary cell.Separate and extend the ability of this population at cancer and the bone marrow of genopathy There is in transplanting clinical practice.Small etc. (Proc.Nat.Acad.Sci.1994,91:459-463) have cloned self enrichment The human homolog of cDNA muroid Flk2/Flt3 of the stem cell tyrosine kinase 1 of CD34+ hemopoietic stem cell bank.cDNA Coding and muroid homologue have 993 amino acid whose protein of 85% homogeneity and 92% similarity.It is equal to FLT3's STK1 is the member of type III receptor tyrosine kinase family, and this family includes KIT, FMS and comes from hematoblastic growth factor receptor Body.STK1 in human blood and bone marrow expresses and is limited in what CD34+ cell was enriched with in a large number by stem/progenitor cells Population.The antisense oligonucleotide suppression hematopoietic colonies of inverse STK1 sequence orientation is formed, and suppresses the strongest on long-term bone marrow is cultivated Strong.Data display STK1 can play effect (the OMIM MIM of growth factor receptors on hematopoietic stem cell and/or CFU-GM Number:136351:03/03/2005).
Levis etc. claim receptor tyrosine kinase FLT3 Internal tandem sequence repeats (ITD) sudden change 20% to 30% patient with acute myeloid leukemia (AML) finds.These sudden changes substantially have activated receptor and seem Prognosis with difference is relevant.In their research, the test of dose response cytotoxin is at the primary embryo cell of the patient with AML On carry out with AG1295, AG1295 is the tyrosine kinase inhibitor to FLT3 activity, and they find that AG1295 is for containing The AML blastocyte having FLT3/ITD to suddenly change is specific cell toxin.They propose these sudden change cause leukemia process and In AML, FLT3 receptor represents therapeutic target (Levis etc., Blood 2001,98:885-887).Flt3 inhibitor can be used for treating Acute myeloid leukemia, myelodysplasia syndrome, polarity Lymphocytic leukemia.
Kinase activity assays
The most different Kinase activity assays can be used, be used for analyzing active regulator and/or determining that regulator is to tool Body kinases or the specificity of kinases group.In addition to test mentioned in embodiment below, those of ordinary skill in the art can Easily verify that other test that can be used, and can be for concrete application amendment test.Such as, relate to kinase whose in a large number Paper describes the test that can be used.
Optional mensuration additionally can use combination to identify.Such as, this kind of mensuration can be designed as FRET (fluorescence resonance energy transfer) (FRET) pattern or be connected to the donor on Succ-PEG-DSPE or phosphorus specific antibody and receptor agents by change And use AlphaScreen (to amplify luminescent proximity homogenizing to measure, amplified luminescent proximity Homogeneous assay) pattern.
Organic synthesis technology
There is substantial amounts of organic synthesis technology in the prior art, to help the structure of potential regulator.These organic conjunctions Many kind in one-tenth method is encyclopaedized in the Standard reference works used by those skilled in the art is originated.Such reference One example of document is March, 1994,Advanced Organic Chemistry；Reactions, Mechanisms and Structure, New York, McGraw Hill.Therefore, for synthesizing the technology pair of the potential regulator of kinase function It is readily available for the technical staff in organic chemical synthesis field.
Optional compound form or derivant
With reference to formula and particular compound, the compound considered herein is described.Additionally, invention compound can with many not With form or derivant exist, all these be within.Optional form or derivant include such as (a) Prodrug and active metabolite (b) tautomer, isomer (including stereoisomer and regional isomer) and raceme Mixture (c) pharmaceutically acceptable salt and (d) solid form, it includes different crystal form, polymorph or amorphous solids, It includes its hydrate and solvate and other form.
(a) prodrug and metabolite
In addition to as herein described chemical formula and compound, the present invention also includes prodrug (the most pharmaceutically Acceptable prodrug), active metabolism derivant (active metabolite) and their pharmaceutically acceptable salt.
Required activation is produced by solvolysis when when prodrug is metabolism in physiological conditions or being converted The compound of compound or its pharmaceutically acceptable salt.Prodrug includes but not limited to: the ester of reactive compound, amide, ammonia Carbamate, carbonic ester, uride, solvate or hydrate.Usually, prodrug is inactive or its activity is less than Reactive compound, but process, administration and/or the metabolisming property that one or more are favourable can be provided.Such as, some prodrug It it is the ester of reactive compound；During metabolism, ester group is cut and produces active medicine.Ester, including, the ester of such as hydroxy-acid group Or the S-acyl group of mercaptan, ethanol or phenolic groups or O-acyl derivative.In this context, common example is the alkane of carboxylic acid Base ester.Prodrug may also include such variant, and wherein-NH the group of compound has experienced acylation, such as herein 7 or the 1-position of 1H-pyrrolo-[2,3-b] pyridine ring, wherein acyl group base of pyrrolo-[2, the 3-d] pyrimidine ring of described compound The decomposition of group provides the free-NH groups of active medicine.Some prodrug enzyme activations produce reactive compound, or chemical combination Thing can experience further chemical reaction, produces reactive compound.Prodrug can be in a single step from prodrug form Be processed as activity form, maybe can have one or more intermediate forms, described intermediate forms self can active or Can be inactive.
Such as The Practice of Medicinal Chemistry, Ch.31-32 (Ed.Wermuth, Academic Press, San Diego, CA, 2001) described in, conceptually, prodrug is divided into the kind of two exhaustive: raw Thing precursor medicine (bioprecursor prodrugs) and precursor carrier medicine.Usually, bioprecursor prodrug is Inactive or compare the active pharmaceutical compounds low compound of activity of correspondence, it contains one or more blocking group And it is converted into activity form by metabolism or solvolysis.Active drug form and any metabolite being released All should have acceptable hypotoxicity.Usually, the formation of active pharmaceutical compounds relates to the metabolism of one of following classes Journey or reaction:
Oxidation reaction: oxidation reaction example for and be not limited to following reaction: such as the oxidation of alcohol, carbonyl and acid functional group, fat The hydroxylating of race's carbon, the hydroxylating of alicyclic ring carbon atom, the oxidation of aromatic carbon atom, the oxidation of carbon-carbon double bond, nitrogen-containing functional group Oxidation, the oxidation of silicon, phosphorus, arsenic and sulfur, oxidisability N-dealkylation, oxidisability O-and S-dealkylation, oxidisability deaminizating, with And other oxidation reaction.
Reduction reaction: reduction reaction example for and be not limited to following reaction: as the reduction of carbonyl functional group, alcohol functional group and The reduction of carbon-carbon double bond, the reduction of nitrogen-containing functional group and other reduction reaction.
The reaction that oxidation state does not change: the reaction example that oxidation state does not changes for and be not limited to following reaction: as Ester and the hydrolysis of ether, the hydrolytic cleavage of carbon nitrogen singly-bound, the hydrolytic rupture of non-aromatic heterocyclic, carry out in the position of multiple keys hydration and Dehydration, dehydration the new atom keyed jointing obtained, hydrolyze the dehalogenation reaction, the removal of hydrogen halides molecule is this kind of instead with other Should.
Precursor carrier medicine is the medical compounds containing transport section (transport moiety), described part example As, improve picked-up and/or carry to the local of site of action (one or more).This precursor carrier medicine be it is desirable for Key between drug moiety and transport section is covalent bond, and prodrug is inactive or to compare medical compounds activity low, front The transport section of body medicine and any release is the most nontoxic.Transport section is intended to strengthen the precursor medicine of picked-up Thing, typically, the release of transport section should be rapid.In other cases, it is desirable to utilize the part that slowly release is provided, Such as, some polymer or other parts, such as cyclodextrin.(see for example Cheng etc., United States Patent (USP) discloses 20040077595, Application number 10/656,838, is incorporated herein by reference).This precursor carrier medicine is to have generally for the medicine that per os gives Profit.In some cases, transport section provides the orientation transport of medicine, and such as medicine can conjugate to antibody or antibody fragment On.Such as, precursor carrier medicine may be used for improving one or more in following character: the lipotropy of increase, the medicine of increase The improvement of reason duration of effect, the site specific of increase, the toxicity of reduction and adverse effect and/or pharmaceutical preparation is (such as, Stability, water solublity, unwanted organ sensation or the suppression of physicochemical property).Such as, by with lipotropy carboxylic esterification hydroxyl Base, or it is esterified hydroxy-acid group with alcohol such as aliphatic alcohol, lipotropy can be increased.Wermuth, see on.
Metabolite, such as active metabolite, and above-mentioned prodrug, such as bioprecursor prodrug are overlapping.Thus, this Kind of metabolite be pharmaceutically active compounds or further metabolism be the compound of pharmaceutically active compounds, it is to be produced from subject The derivant of intracellular metabolite process.Wherein, active metabolite is this pharmacologically active derivative compound.For prodrug, precursor Medical compounds is typically inactive or specific activity metabolite is low.For active metabolite, parent compound can be activity Compound can be maybe inactive precursor medicine.Such as in some compounds, one or more alkoxy bases can be metabolized Retain pharmacologically active for oh group, and/or carboxyl can be esterified, such as glucuronidation.In some cases, one can be had more than Planting metabolite, wherein, intermediate metabolites (one or more) can be by further metabolism, to provide active metabolite.Such as one In a little situations, being produced from the derivative compound of metabolism glucuronidation can be inactive maybe can to have low activity, and can be entered One step metabolism, to provide active metabolite.
Use routine techniques known in the art, it is possible to identify the metabolite of compound, and use as described herein that A little their activity of test determination.See, such as Bertolini etc., 1997, J.Med.Chem., 40:2011-2016；Shan etc., 1997, J Phartn Sci 86 (7): 756-757；Bagshawe, 1995, Drug Dev.Res., 34:220-230； Wermu1H, see on.
(b) tautomer, stereoisomer and regional isomer
It should be understood that some compounds can show tautomerism.In this case, formula provided herein is obvious Only describe the one in possible tautomeric form.It should therefore be understood that described formula provided herein is intended to generation Any tautomeric form of the compound described by table, is not limited solely to the concrete tautomerism shape described by structural formula accompanying drawing Formula.
Equally, can exist as stereoisomer according to some in the compound of the present invention, i.e. they have covalency Same atoms in conjunction with atom connects, but the direction in space of atom is different.Such as, compound can be comprise one or more The optical stereoisomeric forms of chiral centre, therefore, it can as two or more stereoisomeric forms in any ratio exist (such as, mapping is different Structure body or diastereomer).Therefore, this compound can (that is, be substantially free of other to stand as single stereoisomers Body isomer), racemic modification and/or enantiomer and/or the mixture of diastereomer and exist.As another example Son, stereoisomer comprises geometry isomer, if the substituent group on the adjacent carbons of double bond is cis or trans direction.All This single stereoisomers, racemic modification and mixture thereof are intended to encompass within the scope of the present invention.Without indicating on the contrary, All this stereoisomeric forms in any ratio are comprised in formula provided herein.
In some embodiments, the chipal compounds of the present invention is to contain the individual isomer (60% of at least 80% Enantiomer excess (" e.e. ") or diastereomer excess (" d.e. ")) form, or at least 85% (70%e.e. or D.e.), 90% (80%e.e. or d.e.), 95% (90%e.e. or d.e.), 97.5% (95%e.e. or d.e.) or 99% (98%e.e. or d.e.).Such as those skilled in the art it is generally understood that the optical pure compound with a chiral centre is base By a kind of compound (that is, enantiomer-pure) constituted in two kinds of possible enantiomers in basis, there is more than one hands The optical pure compound at property center is the compound of the pure and mild enantiomer-pure of non-enantiomerism.In some embodiments, chemical combination Thing presented in optical voidness, this optical voidness form by method as known in the art (such as by recrystallization technology, Chiral synthesis techniques (including synthesizing from optical voidness parent material) and the chromatography of use chiral column) prepare and/or separate.
(c) pharmaceutically acceptable salt
Unless indicated to the contrary, the explanation of compound herein includes the pharmaceutically acceptable salt of this compounds.Thus, Compound described herein to be the form of pharmaceutically acceptable salt or can be formulated as pharmaceutically acceptable salt.Consider Pharmaceutically acceptable salt form includes but not limited to mono-salt, disalt, three salt, four salt etc..Pharmaceutically acceptable salt is at them It is nontoxic under the amount used and concentration.The preparation of this salt does not hinder it to show it by changing the physical property of compound Physiological effect, can promote that pharmacology utilizes.Change useful in physical property include reduce fusing point with promote mucosal administration and Increase dissolubility to promote to use the medicine of higher concentration.The compound of the present invention can have enough acid functional group, enough The functional group of alkalescence or Liang Zhong functional group, and thus can arbitrary with many inorganic bases or organic base and mineral acid or organic acid Plant reaction, to form pharmaceutically acceptable salt.
Pharmaceutically acceptable salt includes acid-addition salts, such as, comprise following those: chloride, bromide, iodide, Hydrochlorate, acetate, phenylacetate, acrylates, Ascorbate, aspartate, benzoate, 2-phenoxy benzoic acid Salt, Aspirin salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, ar-Toluic acid Salt, bicarbonate, butine-Isosorbide-5-Nitrae-diacid salt, hexin-1,6-diacid salt, caproate, caprylate, chloro benzoate, cinnamic acid Salt, citrate, caprate, formates, fumarate, glycol hydrochlorate, gluconate, glucosaccharic acid salt, glucuronate, G-6-P salt, glutamate, Glu, enanthate, caproate, isethionate, isobutyrate, gamma hydroxybutyrate, phenyl Butyrate, lactate, malate, maleate, hydroxymaleic acid salt, citraconic acid salt, malonate, mandelate, Nicotinate, nitrate .gamma.-pyridinecarboxylic acid salt, caprylate, oleate, oxalates, embonate, phosphate, dibasic alkaliine, phosphoric acid Dihydric salt, orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglyceric acid salt, glycerol 3-phosphate hydrochlorate, phthalate, propanoic acid Salt, phenpropionate, propiolate, pyruvate, quinate, salicylate, 4-ASA salt, sebacate, tristearin Hydrochlorate, suberate, succinate, sulfate, pyrosulfate, disulfate, sulphite, bisulfites, sulfamic acid Salt, sulfonate, phenylbenzimidazole sulfonic acid salt (i.e. benzene sulfonate), ethane sulfonate (i.e. esilate), ethane-1,2-disulfonate, 2- Hydroxyethanesulfonic acid salt (i.e. isethionate), methane sulfonates (i.e. mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt (i.e. naphthalene sulfonate), propane sulfonic acid salt, tosilate (i.e. toluene fulfonate), xylenesulfonate, cyclohexylsulfamic Salt, tartrate and trifluoroacetate.Suitable relative acid can be used to prepare these pharmaceutically acceptable acid-addition salts.
When there is acidic functionality such as carboxylic acid or phenol, pharmaceutically acceptable salt also includes base addition salts, such as, comprises Those following salt: benzathine benzylpenicillin, chloroprocaine, choline, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, bicyclo- Hexylamine, ethylenediamine, N, N '-dibenzyl-ethylenediamin, meglumine, hydroxyethyl hydroxyethyl, piperidines, morpholine, piperazine, procaine, aluminum, Calcium, copper, ferrum, lithium, magnesium, manganese, potassium, sodium, zinc, ammonium and mono-, di-or trialkylamine (such as diethylamide) or be derived from aminoacid such as L- Histidine, 1B, the salt of L-arginine.Such as, see Remington ' s Pharmaceutical Sciences, 19thEd., Mack Publishing Co., Easton, PA, Vol.2, p.1457,1995.Suitable corresponding alkali can be used, Prepare these pharmaceutically acceptable base addition salts.
Pharmaceutically acceptable salt can be prepared by standard technique.Such as, the free alkali form of compound may be dissolved in conjunction Suitable solvent such as contains in suitable aqueous acid or aqueous ethanol solution, and then passes through evaporation solution separating.At another In example, can be by making free alkali and acid reaction prepare salt in organic solvent.If particular compound is acid, can be by any Suitably method, such as, process free acid with suitable inorganic or organic base, prepare desired pharmaceutically acceptable salt.
(d) other compound form
In the case of reagent is solid, it will be appreciated by those skilled in the art that compound and salt can be with different crystalline substances Body or polymorphic exist, or can prepare as eutectic, can be maybe amorphous forms, can be maybe its any combination (such as Partially crystallizable, part amorphous or polymorphous mixture), all these intentions fall in the present invention and the scope of appointment formula In.Although being added by acid/base and being shaped as salt, the free alkali of compound interested or free acid respectively with corresponding addition alkali Or addition of acid forms acid/base reaction, cause ionic charge to interact, but eutectic is a kind of formation between neutral compound New chemical species, produces compound and other molecular species of same crystal structure.
In some cases, the compound of the present invention is combined with acid or alkali, including: base addition salts, such as ammonium, diethylamine, Ethanolamine, ethylenediamine, diethanolamine, tert-butylamine, piperazine, meglumine；Acid-addition salts, such as acetate, acetylsalicylate, benzene Sulfonate, d-camphorsulfonic acid salt (camsylate), citrate, formates, fumarate, glutarate, hydrochlorate, Maleate, mesylate, nitrate, oxalates, phosphate, succinate, sulfate, tartrate, rhodanate and first Benzene sulfonate；And aminoacid, such as alanine, arginine, agedoite, aspartic acid, cysteine, glutamine, paddy Propylhomoserin, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, Soviet Union Propylhomoserin, tryptophan, tyrosine or valine.Be combined in the compound of the present invention with acid or alkali, be preferably formed as amorphous compound The such as typical salt of thing rather than crystalline material or eutectic.In some cases, by extra processed, such as by spray Mist is dried, mechanochemistry method such as rolls or be mixed with the microwave radiation of parent compound of acid or alkali, promotes the nothing of complex Amorphous form.This method may also include the addition of ionically and/or non-ionically polymer system, this polymer system include but not It is limited to hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymer (such as LI00-55), the amorphous property of its further stable compound.This amorphous complex provides several advantages.Such as, molten Melting temperature and reduce the most extra course of processing relative to free alkali, such as hot-melt extruded, to improve compound further Biological pharmacology character.And, amorphous complex is fragile, and this provides the extruding of improvement, it is simple to solid is loaded capsule Or in tablet form.
It addition, chemical formula is intended to cover the hydration of indication structure or solvation form and non-hydrated or non-solvated shape Formula.Such as, the compound of indication includes both hydrated form and nonhydrated form.Other example of solvate includes described knot Structure combines suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine.
Preparation and using
Described method and compound can be typically used in the treatment of people's object.But, they can be additionally used in moves at other The indication that in thing object, treatment is similar or identical.Compound described herein can be used by different approach, described approach Including injection (i.e. parenteral, including vein, goldbeater's skin, subcutaneous and muscle), it is administered orally, through skin, through mucous membrane, rectum or suction.This Planting dosage form should make compound arrive target cell.Other factors is known in the art, and includes Consideration, such as toxicity and Compound or compositions is delayed to play the dosage form of its effect.Technology and preparation typically can be found in Remington:The Science And Practice of Pharmacy, 21stVersion, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (being incorporated herein by reference herein).
In some embodiments, compositions can comprise pharmaceutically acceptable carrier or excipients such as filler, glue Mixture, disintegrating agent, fluidizer, lubricant, complexant (complexing agent), cosolvent and surfactant, it can quilt Select to promote by particular approach administered compound.The example of carrier includes calcium carbonate, calcium phosphate, various sugar such as lactose, Portugal Grape sugar or sucrose, starch type, cellulose derivative, gelatin, lipid, liposome, nano-particle etc..Carrier also includes as molten Agent or for the liquid of PHYSIOLOGICALLY COMPATIBLE suspended, including the sterile solution of such as water for injection (WFI), saline solution, glucose Solution, Hank solution, Ringer solution, vegetable oil, mineral oil, animal oil, Polyethylene Glycol, liquid paraffin and analog.Figuration Agent may also include such as colloidal silica, silica gel, Pulvis Talci, magnesium silicate, calcium silicates, sodium aluminosilicate, magnesium trisilicate, powdery fibre Dimension element, macrocrystalline cellulose, carboxymethyl cellulose, the sodium carboxymethyl cellulose of crosslinking, sodium benzoate, calcium carbonate, magnesium carbonate, tristearin Acid, aluminium stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, flatting silica, stearowet C, oxidation Magnesium, starch, sodium starch glycol, glyceryl monostearate, two Glyceryl Behenates (glyceryl dibehenate), Petiolus Trachycarpi Acid tristerin, hydrogenated vegetable oil, cotmar, Semen Ricini oil, mineral oil, Polyethylene Glycol (such as PEG 4000- 8000), polyoxyethylene glycol, poloxamer, polyvidone, crospovidone, cross-linked carboxymethyl cellulose sodium, alginic acid, casein, first Base acrylic acid-divinyl benzene copolymer, docusate sodium, cyclodextrin (such as 2-hydroxypropyl-δ-cyclodextrin), polysorbate (such as polysorbate 80), cetyl trimethylammonium bromide (cetrimide), TPGS (d-alpha-tocopherol cetomacrogol 1000 Succinate), Stepanol MG, sodium lauryl sulphate, polyglycol ether, the di fatty acid ester of Polyethylene Glycol or poly- Oxygen ethylene sorbitan fatty acid ester (such as polyoxyethylene sorbitol ester), polyoxyethylene sorbitol fatty acid Ester, sorbitan fatty acid ester are such as from fatty acid such as oleic acid, stearic acid or the sorbitan fatty acid ester of Palmic acid, sweet Dew alcohol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or the lactose of spray drying, sucrose, fructose, calcium phosphate, Calcium hydrogen phosphate, tertiary calcium phosphate, calcium sulfate, dextrates (dextrate), glucosan, dextrin, glucose, acetate fiber Element, maltodextrin, Simethicone, polydextrose (polydextrosem), chitosan, gelatin, HPMC (hydroxypropyl methyl fiber Element), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose etc..
In some embodiments, can use Orally administered.Pharmaceutical preparations for oral can be configured to the mouth of routine Oral dosage form, such as capsule, tablet and liquid preparation, such as syrup, elixir and concentration drop.Compound described herein can be with solid Excipient combines, and optionally grinds the mixture of generation, and if so desired, is adding the mixing of suitable auxiliary agent post processing granule Thing, to obtain such as tablet, coated tablet, hard capsule, soft capsule, solution (such as aqueous solution, ethanol solution or oil solution) etc.. Suitably excipient is especially filler, such as sugar, including lactose, glucose, sucrose, mannitol or sorbitol；Cellulose Preparation, such as corn starch, wheaten starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl Ylmethyl cellulose, sodium carboxymethyl cellulose (CMC) and/or polyvinylpyrrolidone (PVP: polyvidone (povidone))；Oil Property excipient, including vegetable oil and animal oil, such as Oleum Helianthi, olive oil or cod-liver oil.Dosage formulation also can be containing collapsing Solve agent, the polyvinylpyrrolidone such as cross-linked, agar or alginic acid or their salt, such as sodium alginate；Lubricant, such as Talcum Or magnesium stearate；Plasticizer, such as glycerol or sorbitol；Sweeting agent, such as sucrose, fructose, lactose or aspartame；Natural or Artificial flavors, such as Herba Menthae, wintergreen oil or Fructus Pruni pseudocerasi flavoring agent；Or dyestuff or pigment, they are different for identifying or characterizing Dosage or combination.Additionally provide the dragee (dragee core) with suitable coating.For this purpose, concentration can be used Sugar juice, it can optionally contain, such as arabic gum, Talcum, polyvinylpyrrolidone, Carbopol gel, Polyethylene Glycol and/ Or titanium dioxide, paint solution and suitably organic solvent or solvent mixture.
The pharmaceutical preparation of orally available use includes push style (push-fit) capsule being made up of gelatin (" gelcaps "), And the soft seal capsule being made up of gelatin and plasticizer such as glycerol or sorbitol.Push style capsule can contain active one-tenth Point, it is with filler such as lactose, binding agent such as starch and/or lubricant such as Talcum or magnesium stearate, and optional steady Determine agent mixing.In soft capsule, reactive compound can be dissolved or suspended in suitable liquid such as fatty oil, liquid paraffin or In liquid macrogol.
In some embodiments, it is possible to use injection (parenteral administration), such as intramuscular, intravenous, intraperitoneal And/or subcutaneous.Compound described herein for injection can be formulated as sterile aqueous solutions, preferably delaying at PHYSIOLOGICALLY COMPATIBLE Rush in liquid or solution such as saline solution, Hank ' s solution or Ringer ' s solution.Can be at non-aqueous solution, such as glycerol, the third two Alcohol, ethanol, liquid macrogol, glyceryl triacetate and vegetable oil are prepared dispersion.Solution also can contain preservative, such as oxybenzene first Acid methyl ester, propylparaben, methaform, phenol, sorbic acid, thiomersalate etc..It addition, compound can be by It is formulated as solid form, including, such as lyophilized form, and re-dissolved or suspension before the use.
In some embodiments, through mucous membrane, local or applied dermally can be used.This system at compound described herein In agent, use and treat the penetrating agent that permeability barrier is suitable.Such penetrating agent is commonly known in the art, such as Mucosal administration, including bile salts and fusidic acid derivatives.It addition, cleaning agent may be used for promoting infiltration.Such as, through mucous membrane Use and can be sprayed by nose or suppository (per rectum or vagina).By selecting suitable carrier known in the art, for local The compositions of the compound described herein used can be formulated as oil, Emulsion, lotion, unguentum etc..Suitably carrier includes vegetable oil Or mineral oil, white oil (White soft paraffin), Branched fatty or oil, Animal fat and high molecular weight alcohol (C12Above).One In a little embodiments, select carrier so that active component is solvable.If so desired, may also include emulsifying agent, stabilizer, wetting agent and Antioxidant and give color or the preparation of fragrance.The Emulsion that local uses is preferably from mineral oil, self emulsifying beeswax and water Mixture preparation, the active component being dissolved in in a small amount solvent (such as oil) is mixed in the mixture.Additionally, percutaneous side Formula is used and can be included transdermal skin patches or dressing, as being impregnated with active component and one or more carriers the most known in the art Or the binder of diluent.In order to use with transdermal delivery system form, it is continuous print that the dosage during dosage regimen is used, and not It is to be interrupted.
In some embodiments, compound is used as inhalant.Compound described herein can be formulated as dry powder or conjunction Suitable solution, suspension or aerosol.Appropriate addn known in the art preparation powder and solution can be used.Such as, powder Can include suitable powdered substrate (powder base) such as lactose or starch, and solution can comprise propylene glycol, aseptic Water, ethanol, sodium chloride and other additive such as acid, alkali and buffer salt.Can pass through through spraying, pump, aerosol apparatus or nebulizer etc. This solution or suspension are used in suction.Compound described herein can also with other anapnotherapy connected applications, described other Anapnotherapy is such as: corticosteroid such as FLUTICASONE PROPIONATE, beclomethasone dipropionate, KENALOG (triamcinolone Acetonide), BUDESONIDE and mometasone furoate (mometasone furoate)；Beta-agonists such as albuterol, Sha Meite Sieve and formoterol；Anticholinergic such as SCH 1000 (ipratroprium bromide) or thiophene torr (tiotropium)； Vasodilation such as treprostinal and iloprost (iloprost)；Enzyme such as DNA enzymatic；Human cytokines；Immunity ball Protein antibodies；Oligonucleotide such as strand or double-stranded DNA or RNA, siRNA；Antibiotic such as tobramycin；M-ChR antagonism Agent；Leukotriene antagonist；Cytokine antagonist；Protease inhibitor；Sodium cromoglicate (cromolyn sodium)；Nai Duoluo Rice sodium (nedocril sodium) and cromoglycate sodium (sodium cromoglycate).
Be may determine that the amount of various compounds to be administered by standardization program, it is considered to the activity of factor such as compound (external, such as compound IC50 is to target；Or internal, activity in Animal potency model), medicine in animal model is for power Learn result (such as biological half-life or bioavailability)；The age of object, size and body weight and the disease relevant with object. Known to the importance of these factors and other factors is for those of ordinary skill in the art.It is said that in general, dosage is at quilt Between the about 0.01mg/kg to 50mg/kg for the treatment of target, also between about 0.1mg/kg to 20mg/kg.Can use many Secondary dosage.
Compound described herein may also be combined with the other therapies for the treatment of same disease and uses.This being used in combination is included in not Same time administered compound and one or more other therapies, or administered compound and one or more other therapies altogether.? In some embodiments, by method well known within the skill of those ordinarily skilled, one or more chemical combination of the present invention can be changed Thing or the dosage of other therapies being used in combination, such as, reduce dosage relative to the compound being used alone or therapy.
Should be appreciated that to be used in combination and include being used together with other therapies, medicine, medical procedure etc., wherein other therapies Or operation can from compound described herein different time (such as within a short period of time, such as a few hours (such as 1,2,3, 4-24 hour) in or longer time (such as 1-2 days, 2-4 days, 4-7 days, 1-4 week) in) use, or with chemical combination described herein Thing was used in the identical time.In conjunction with using the therapy also included and use once or use once in a while or medical procedure such as surgery hands Art, together with the compound described herein used between other therapies or operation or in the short time afterwards or in the longer time Use.In some embodiments, the present invention provides through this paper that different approaches is used or used conveying by identical approach Described compound and the conveying of one or more pharmacotherapys.The combination of any route of administration is used and is included in any preparation In the compound described herein that carried by identical approach together and the conveying of one or more pharmacotherapys, described preparation includes The two of which compound preparation that they are connected chemically in the way of keeping their therapeutic activity in time using.In one aspect, Other medicines therapy and compound described herein can be used altogether.Included by identical or different by being used in combination of using altogether Approach is used, and uses common preparation or the preparation of chemical bond compound, or the short time (such as 1 hour, 2 hours, 3 hours, Until 24 hours) in the two or more compound that is applied in preparation independent of each other.The using altogether of independent formulations include through A kind of equipment, the most identical inhalation device, identical syringe etc. are used altogether by conveying, or at short notice from the most only Vertical equipment is used.Compound described herein is executed altogether with one or more the other medicines therapies carried by identical approach With including preparing together material, in order to they can include, by a kind of equipment, the isolated compound that is combined in a kind of preparation Or modified so as they chemical bond but still keep its bioactive compound to use.This chemically combined compound Can have the connection being kept substantially in vivo, or connect and can rupture in vivo, be broken up into two active components.
Embodiment
Described below relate to embodiments of the invention.In major part situation, the technology being replaced with can be made.These are implemented Example be intended to be illustrative rather than define or limit the scope of the present invention.In certain embodiments, the matter of compound is described Spectrum result can have more than one value, and its reason is the Isotopic Distribution of atom in the molecule, as having bromine or chlorine substituent Compound.Compound in the following example passes through1H and13C NMR spectra and mass spectral characteristi.
Unless otherwise specified, the formula for following example enumerate enumerate with R group be not related to the application its This in its part is enumerated.The reagent and the solvent that use in these embodiments can hold with suitable substitute known in the art Change places replacement, and the separation of product easily realized by methods known in the art, described method include but not limited to extraction, Crystallization and chromatography method.
The ring numbering of 1H-pyrrolo-[2,3-b] pyridine is as follows in the following embodiments:
The ring numbering of 7H-pyrrolo-[2,3-d] pyrimidine is as follows in the following embodiments:
The synthesis of the chloro-3-of embodiment 1:5-iodo-1H-pyrrolo-[2,3-b] pyridine 2.
As shown in scheme 1, the chloro-3-of 5-iodo-1H-pyrrolo-[2,3-b] pyridine 2 is from 5-chloro-1H-pyrrolo-[2,3- B] pyridine 1 prepared in one step.
Scheme 1
The preparation of step 1-5-chlorine 3-iodo-1H-pyrrolo-[2,3-b] pyridine (2):
In nitrogen, in 20 minutes the chloro-1H-of the 5-in 300mL dichloromethane pyrrolo-[2,3-b] pyridine (1, 15.00g, 98.31mmol) solution is slowly added into pyridine (7.951mL, 98.31mmol) and iodine monochloride (110mL, dichloromethane 1.0M in alkane, 110mmol).It is stirred at room temperature reaction 2 hours, is then hydrated with the aqueous sodium thiosulfate five of 100mL 1M Thing cancellation.Separating this layer, solid by filtration is collected from water layer and is combined with organic layer.Aqueous layer with ethyl acetate extracts, Organic layer is combined, and washs with saline, is then concentrated under vacuum.20% ethyl acetate in the solid hexane obtained Washing is to provide desired compound.The 5-iodo-1H-pyrroles of fluoro-3-is prepared similarly from 5-fluoro-1H-pyrrolo-[2,3-b] pyridine And [2,3-b] pyridine.
The synthesis of the chloro-3-of embodiment 2:5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 4.
As shown in scheme 2, the chloro-3-of 5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 4 is from 5- Chloro-3-iodo-1H-pyrrolo-[2,3-b] pyridine 2 is prepared in one step.
Scheme 2
The preparation of the chloro-3-of step 1-5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (4):
The chloro-3-of 5-iodo-1H-pyrrolo-[2,3-b] pyridine in 250.0mL DMF (2, 16.50g, 59.25mmol) in add sodium hydride (3.10g, in mineral oil 60%, 77.5mmol).Reaction is stirred at room temperature 90 Minute, then it is slowly added into triisopropylsilyl chloride (3,13.00mL, 61.36mmol).Reaction is stirred at room temperature Overnight, it is subsequently poured in water and is extracted with ethyl acetate.Organic layer is dried over sodium sulfate, and filtration and filtrate are under vacuo Concentrate.The material obtained is purified by silica gel column chromatography, the 20-100% acetic acid second in described silica gel column chromatography hexane Ester eluting.Suitably fraction is combined and is concentrated under vacuum to provide desired compound (4,10.0g).Similarly, from 5- The fluoro-3-of 5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyrrole prepared by fluoro-3-iodo-1H-pyrrolo-[2,3-b] pyridine Pyridine.
With the method being similar to scheme 2, with 3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine, 3-iodo-5-trifluoro Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine and 3-iodo-4-methoxyl group-1H-pyrrolo-[2,3-b] pyridine replace the chloro-3-of 5-respectively Iodo-1H-pyrrolo-[2,3-b] pyridine 2, preparation 3-iodo-5-methoxyl group-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] Pyridine 5,3-iodo-5-Trifluoromethyl-1-tri isopropyl silane iodo-4-methoxyl group of base-1H-pyrrolo-[2,3-b] pyridine 6 and 3-- 1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 7
MS(ESI)[M+H+]+=431.2 (compounds 5) and 469.4 (compounds 6).
The synthesis of embodiment 3:3-iodo-5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 9.
As shown in scheme 3,3-iodo-5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 9 be from 5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,34] pyridine 8 is prepared in one step.
Scheme 3
The preparation of step 1-3-iodo-5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (9):
5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (8,1.1g, 3.8mmol) and 10mL bis- Chloromethanes is combined and stir 10 minutes in round-bottomed flask.Add the N-N-iodosuccinimide in 5mL dichloromethane The serosity of (1.0g, 4.6mmol) is also stirred at room temperature overnight.Reaction with sodium thiosulfate (20mL, 1M in water) cancellation and Aqueous layer with ethyl acetate extracts.In conjunction with organic layer water and saline washing, be dried with sodium sulfate, filter and filtrate in vacuum Lower concentration.The material obtained is purified by silica gel column chromatography, described silica gel column chromatography ethyl acetate and Hex.Close Suitable fraction is combined and is concentrated under vacuum to be provided as the expectation compound (9,1.2g, 75%) of faint yellow oil.MS(ESI) [M+H+]+=415.08.
The synthesis of embodiment 4:3-iodo-5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine 10.
As shown in scheme 4,3-iodo-5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine 10 is from 5-methyl isophthalic acid-triisopropyl Silylation-1H-pyrrolo-[2,3-b] pyridine 8 is prepared in one step.
Scheme 4
The preparation of step 1-3-iodo-5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine (10):
5-methyl isophthalic acid in 10mL oxolane-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (8,1g, 2.0mmol) solution adds the iodine (0.43g, 1.7mmol) in 5mL oxolane.Reaction is stirred at room temperature overnight, then With 20mL 1M aqueous sodium thiosulfate cancellation and be extracted with ethyl acetate.Organic layer is combined and washs with water, saline, It is dried on sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described silicon Plastic column chromatography ethyl acetate and Hex.Suitably fraction is combined and is concentrated under vacuum to be provided as white solid Expect compound (10,20mg).MS(ESI)[M+H+]+=258.70.
The synthesis of the chloro-3-of embodiment 5:1-benzenesulfonyl-5-iodo-1H-pyrrolo-[2,3-b] pyridine 12.
As shown in scheme 5, the chloro-3-of 1-benzenesulfonyl-5-iodo-1H-pyrrolo-[2,3-b] pyridine 12 is from the chloro-3-of 5- Iodo-1H-pyrrolo-[2,3-b] pyridine 2 and benzene sulfonyl chloride 11 are prepared in one step.
Scheme 5
The preparation of the chloro-3-of step 1-1-benzenesulfonyl-5-iodo-1H-pyrrolo-[2,3-b] pyridine (12):
The chloro-3-of 5-iodo-1H-pyrrolo-[2,3-b] pyridine in the DMF of 80.0mL (2,5.00g, Solution 18.0mmol) is slowly added into sodium hydride (1.1g, in mineral oil 60%, 27.0mmol).At 0 DEG C, it is added dropwise over 10.0mLN, benzene sulfonyl chloride (11,2.40mL, the 18.8mmol) solution in dinethylformamide.Reactant mixture is at room temperature Stir 15 hours, be subsequently poured in frozen water and be extracted with ethyl acetate.Organic layer saline washs, and is dried over magnesium sulfate, Filter and filtrate is concentrated under vacuum.In the solid hexane obtained, the ethyl acetate washing of 5%, is isolated by filtration also And be dried to provide desired compound (12,5.9g).1H NMR is consistent with compound structure.It is similar to the method, iodo-with 3- 5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine 10 replaces the chloro-3-of 5-iodo-1H-pyrrolo-[2,3-b] pyridine 2, prepares 1-benzene sulfonyl Base-3-iodo-5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine 13
The fluoro-3-of 1-benzenesulfonyl-5-iodo-1H-pyrrole is prepared similarly from the fluoro-3-of 5-iodo-1H-pyrrolo-[2,3-b] pyridine Cough up also [2,3-b] pyridine.
The synthesis of embodiment 6:1-benzenesulfonyl-3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine 16.
As shown in scheme 6,1-benzenesulfonyl-3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine 16 is from 5-first Oxy-1 H-pyrrolo-[2,3-b] pyridine 14 is prepared in two steps.
Scheme 6
The preparation of step 1-3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine (15):
In nitrogen at-40 DEG C, 5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine in 30mL dichloromethane (14, 300mg, 2.0mmol) solution adds iodine monochloride (3mL, 1.0M, 3.0mmol in dichloromethane).Reaction is stirred to room temperature Under, then with 10mL 1M aqueous sodium thiosulfate pentahydrate cancellation.Separate this layer and be extracted with ethyl acetate water layer.Have Machine layer is combined and washs with water, saline, is dried the most over sodium sulfate, with activated carbon decolorizing, filters and filtrate is in vacuum Lower concentration.20% ethyl acetate washing in the solid hexane obtained is to provide desired compound (15,371mg).MS (ESI)[M+H+]+=275.03.
The preparation of step 2-1-benzenesulfonyl-3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine (16):
3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-b] in nitrogen, in 53.6mL DMF Pyridine (15,4.30g, 15.7mmol) solution adds sodium hydride (0.690g, in mineral oil 60%, 17.2mmol).10 minutes After, add benzene sulfonyl chloride (11,2.20mL, 17.2mmol), and cool down this reaction in a water bath.Reactant is introduced in water also And be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is by silica gel column chromatography purification, described silicon 30-100% ethyl acetate eluting in plastic column chromatography hexane.Suitably fraction is combined and is concentrated under vacuum to provide the phase The compound (16,4.60g) hoped.
The synthesis of embodiment 7:5-iodo-4-methyl-7-tri isopropyl silane base-7H-pyrrolo-[2,3-d] pyrimidine 20.
As shown in scheme 7,5-iodo-4-methyl-7-tri isopropyl silane base-7H-pyrrolo-[2,3-d] pyrimidine 20 be from 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine 17 is prepared in two steps.
Scheme 7
The preparation of step 1-4-methyl-7H-pyrrolo-[2,3-d] pyrimidine (18):
4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (17,5.03g, 32.8mmol) in nitrogen, in 100mL toluene Middle addition has [1,1 '-bis-(diphenyl phosphine) ferrocene] of dichloromethane (0.627g, 0.328mmol)) dichloro palladium] (II) 1: 1 complex.After stirring 10 minutes, it is slowly added into methyl-magnesium-bromide (62.9mL, 3.00M, 189mmol in ether).Reaction is 55 Heated overnight at DEG C, is subsequently cooled to-70 DEG C to-80 DEG C and by being added dropwise over ammonium chloride cancellation.It is subsequently adding 1N hydrochloric acid And add saturated sodium bicarbonate by pH regulator to 7-8.Reactant is extracted with ethyl acetate 3 times.In conjunction with the saturated chlorine of organic layer Change ammonium and saline washing, be then dried with magnesium sulfate, filter and filtrate is concentrated under vacuum.The material obtained passes through silica gel Column chromatography purification, described silica gel column chromatography ethyl acetate and dichloromethane eluent, then with methanol and dichloromethane eluent.Close Suitable fraction is combined and is concentrated under vacuum to be provided as the expectation compound (18) of brown solid.MS(ESI)[M+H+]+= 134。
The preparation of step 2-5-iodo-4-methyl-7H-pyrrolo-[2,3-d] pyrimidine (19):
4-methyl-7H-pyrrolo-[2,3-d] pyrimidine (18,0.634g, 4.76mmol) in 50mL dichloromethane adds Enter N-N-iodosuccinimide (1.3g, 5.7mmol) and reaction is stirred at room temperature 45 minutes.Reactant is the denseest Contracting, is subsequently adding ethyl acetate and washs with the aqueous sodium thiosulfate of 1N.Organic layer is dried over sodium sulfate, filter and Filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, the 20-in described silica gel column chromatography hexane 100% ethyl acetate eluting.Suitably fraction is combined and is concentrated under vacuum to provide desired compound (19,0.94g). MS(ESI)[M+H+]+=260.26.
The preparation of step 3-5-iodo-4-methyl-7-tri isopropyl silane base-7H-pyrrolo-[2,3-d] pyrimidine (20):
In nitrogen, 5-iodo-4-methyl-7H-pyrrolo-[2,3-d] pyrimidine in 8mL oxolane (19, 323.6mg, 1.25mmol) in add sodium hydride (57.41mg, in mineral oil 60%, 1.44mmol).Reaction is stirred at room temperature 10 minutes, it is subsequently adding triisopropylsilyl chloride (3,0.304mL, 1.44mmol).It is little that reaction is stirred at room temperature 2 Time, it is subsequently poured in water and is extracted with ethyl acetate.Organic layer is dried over sodium sulfate, and filtration and filtrate are under vacuo Concentrate to provide desired compound.
The synthesis of embodiment 8:5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridine 23.
As shown in scheme 8,5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridine 23 is from 5-iodo-1H-pyrrolo-[2,3- B] pyridine 21 prepared in one step.
Scheme 8
The preparation of step 1-5 cyclopropyl-1H-pyrrolo-[2,3-b] pyridine (23):
5-iodo-1H-pyrrolo-[2,3-b] pyridine (21,0.343g, 1.40mmol), cyclopropyl is combined in reaction vessel Zinc bromide (22,12.6mL, 0.500M, 6.32mmol in oxolane) and [1,3-double (diphenyl phosphine) propane]-Nickel dichloride. (II) (76.2mg, 0.14mmol) and 5.37mL1,4-bis-Alkane.Reaction heated overnight at 100 DEG C, is subsequently adding methanol And react and be concentrated under vacuum.Ethyl acetate and water are injected towards in residue, then by kieselguhr (celite) bed mistake Filter, and wash bed of diatomaceous earth by ethyl acetate.Separating filtrate is also extracted with ethyl acetate water layer.Organic layer is combined and uses saline Washing, is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is pure by silica gel column chromatography Change, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction is combined and is concentrated under vacuum to provide the phase The compound hoped.MS(ESI)[M+H+]+=159.0.
Embodiment 9: intermediate 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-4-is chloro- The synthesis of thiazol-2-yl amine 29.
As shown in scheme 9,5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-4-is chloro- Thiazol-2-yl amine 29 synthesizes in four steps from 2-amino-4-chloro-thiazole-5-formaldehyde 24.
Scheme 9
The synthesis of step 1-(4-chloro-5-formyl thiazole-2-base)-t-butyl carbamate (26):
2-amino-4-chloro-thiazole-5-formaldehyde (24,5.00g, 0.0308mol) in 122mL oxolane adds Bis(tert-butoxycarbonyl)oxide (25,7.38g, 0.0338mol) and 4-dimethylaminopyridine (0.35g, 0.0029mol).React Stir 2 hours at 58 DEG C, be then concentrated under vacuum and purify with silica gel column chromatography, in described silica gel column chromatography hexane 20-80% ethyl acetate eluting.Suitably fraction is combined and is concentrated under vacuum to be provided as the expectation chemical combination of yellow solid Thing (26,7.0g, 87%).
Step 2-5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxy-methyl]-4-is chloro- The synthesis of thiazol-2-yl-t-butyl carbamate (27):
In 10 minutes, the 1-chloro-3-of benzenesulfonyl-5-in the 30.0mL oxolane at-45 DEG C in nitrogen is iodo- 1H-pyrrolo-[2,3-b] pyridine (12,4.40g, 10.5mmol) solution is slowly added into isopropylmagnesium chloride solution (5.4mL, 2.0M in oxolane).Reaction was warmed to-25 DEG C in 30 minutes, is subsequently cooled to-65 DEG C, is subsequently added cold deprotonation Change (4-chloro-5-formyl thiazole-2-base)-t-butyl carbamate, its by nitrogen at-78 DEG C by isopropyl chloride Change magnesium (5.0mL, 2.0M in oxolane) add to (the 4-chloro-5-formyl thiazole-2-base) in 23.0mL oxolane- Prepared by t-butyl carbamate (26,2.51g, 9.55mmol) situ.Reaction warmed to room temperature in 2 hours, was subsequently poured into In aqueous ammonium chloride, and it is extracted with ethyl acetate.Organic layer is dried on anhydrous sodium sulfate, and filtration and filtrate are under vacuo Concentrate.The material obtained is purified by silica gel column chromatography, the 25-100% acetic acid second in described silica gel column chromatography hexane Ester eluting.Suitably fraction is combined and is concentrated under vacuum to provide desired compound (27,3.70g, 60.3%).MS (ESI)[M+H+]+=554.2.
Step 3-[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-4-chloro-thiazole-2- Base] synthesis of-t-butyl carbamate (28):
5-[(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxyl in 15.0mL dichloromethane Base-methyl] the chloro-thiazol-2-yl-t-butyl carbamate of-4-(27,0.200g, 0.32mmol) middle addition triethyl silicane (0.600mL, 376mmol) and trifluoroacetic acid (0.300mL, 3.89mmol).Reaction is stirred at room temperature 3 hours, then concentrates, Pour aqueous potassium carbonate into, and be extracted with ethyl acetate.It is dried organic layer on anhydrous sodium sulfate, filters and filtrate is in vacuum Lower concentration.The material obtained is purified by silica gel column chromatography, the 25-100% acetic acid in described silica gel column chromatography hexane Ethyl ester eluting is to provide desired compound (28,0.155g, 88.7%).MS(ESI)[M+H+]+=538.9.
Step 4-5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-4-chloro-thiazole-2- The synthesis of base amine (29):
[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first in 70.0mL dichloromethane Base) the chloro-thiazol-2-yl of-4-]-t-butyl carbamate (28,4.30g, 7.97mmol) middle addition hydrogen chloride solution (42.0mL, Isosorbide-5-Nitrae-two4.00M in alkane).Reaction is stirred at room temperature 2 days, then concentrates, and with ether and ethyl acetate development with offer Desired compound (29,2.60g, 74.2%).MS(ESI)[M+H+]+=439.0.
According to the method for scheme 9, replace 1-with 1-benzenesulfonyl-3-iodo-1H-pyrrolo-[2,3-b] pyridine in step 2 The chloro-3-of benzenesulfonyl-5-iodo-1H-pyrrolo-[2,3-b] pyridine 12, prepares 5-(1-benzenesulfonyl--pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-4-chloro-thiazol-2-yl amine 30
。MS(ESI)[M+H+]+=404.4.
Embodiment 10: the synthesis of aldehyde reagent.
According to the preparation of following method for manufacturing the aldehyde reagent of compound.
As shown in scheme 10a, 5-fluoro-1-methyl-2-oxo-1,2-dihydro-pyrido-3-formaldehyde 33 is from the fluoro-3-of 5- Iodo-pyridine-2-alcohol 31 is prepared in two steps.
Scheme 10a
The preparation of the fluoro-3-of step 1-5-iodo-1-methyl isophthalic acid H-pyridin-2-ones (32):
The fluoro-3-of 5-iodo-pyridine-2-alcohol (31,200g, 838mmol) in 3000mL acetone is cooled down in ice-water bath.Add Cesium carbonate (354g, 1088mmol), was then added dropwise over iodomethane (58.1mL, 929mmol) in 30 minutes.Reaction is in room temperature Under be stirred overnight.The material that reaction is concentrated under vacuum and is obtained distributes between ethyl acetate and water.Separate aqueous layer is also Regulate to pH 3-4 with 3N hydrochloric acid, be then extracted with ethyl acetate.In conjunction with organic layer be concentrated under vacuum to be provided as greyish white The expectation compound (32,150g, 593mmol, 70.8%) of color solid.
Step 2-5-fluoro-1-methyl-2-oxo-1, the preparation of 2-dihydro-pyrido-3-formaldehyde (33):
The fluoro-3-of 5-iodo-1-methyl isophthalic acid H-pyridin-2-ones (32,120.5g, 476mmol) is dissolved in 2381mL oxolane In and in without water-ice acetone bath, be cooled to-40 DEG C.It is added dropwise over isopropylmagnesium chloride (310mL, 619mmol) and stirring should Mixture 30 minutes.It is subsequently adding the DMF of 92mL and makes mixture be heated to room temperature and be stirred overnight.Instead Then should be concentrated under vacuum by adding the aqueous hydrochloric acid cancellation of 200mL10%.The material obtained passes through silica gel column chromatography Being purified, described silica gel column chromatography is with 100% ethyl acetate eluting.Suitably fraction is combined and is concentrated under vacuum to provide Expectation compound (33,35g, 226mmol, 47.4%) for yellow solid.
As shown in scheme 10b, 5-fluoro-2-methoxv-pyridine-3-formaldehyde 37 is from the bromo-5-of 3-fluoro-2-methoxyl group-pyrrole Pyridine 34 is prepared in three steps.
Scheme 10b
The preparation of step 1-5-fluoro-2-methoxy-nicotinic acid methyl ester (35):
In 2L Paar steel cylinder (Parr bomb), the bromo-5-of 3-fluoro-2-methoxv-pyridine (34,14g, 68.0mmol), three Ethamine (19.10mL, 136mmol) and [1,1 '-bis-(diphenyl phosphine) ferrocene]-) dichloro palladium] (II) (1.443g, Heated overnight under the carbon monoxide of 100psi 1.767mmol) it is incorporated at 100 DEG C with the methanol of 300mL knot.Reaction is in vacuum Lower concentration, residue is dissolved in dichloromethane, and by Silicon stone plunger, described Silicon stone plunger ethyl acetate eluting, to carry For the expectation compound (35,10g, 54.0mmol, 79%) for white solid.
The preparation of step 2-(5-fluoro-2-methoxv-pyridine-3-base)-methanol (36):
5-fluoro-2-methoxy-nicotinic acid methyl ester (35,10g, 54.0mmol) at-78 DEG C, in 200mL oxolane In be added dropwise over lithium aluminium hydride reduction (81mL, 1M, 81mmol in oxolane) stirred for several hour.Be added dropwise in order 3mL water, Sodium hydroxide that 3mL 15% is aqueous and 10mL shrend are gone out this reaction, are subsequently adding the methyl tertiary butyl ether(MTBE) of 200mL.Filter out solid Body and filtrate are concentrated under vacuum to be provided as the expectation compound (36,8g, 50.9mmol, 94%) of white solid.
The preparation of step 3-5-fluoro-2-methoxv-pyridine-3-formaldehyde (37):
(5-fluoro-2-methoxv-pyridine-3-base)-methanol (36,8g, 50.9mmol) in 300mL ethyl acetate adds Enter manganese oxide (IV) (39.8g, 458mmol) and mixture is stirred at room temperature overnight.Reaction mixing is filtered by kieselguhr Thing, and use ethyl acetate rinse bed of diatomaceous earth.Filtrate is concentrated under vacuum, then by Silicon stone plunger, and described Silicon stone plunger With 50% ethyl acetate eluting in heptane be provided as faint yellow solid expectation compound (37,4.5g, 29.0mmol, 57.0% yield).
As shown in scheme 10c, (the fluoro-benzyl of 2-)-(5-Formyl-pyridin-2-base)-t-butyl carbamate 42 be from Prepare three steps from the 5-fluoro-benzaldehyde 39 of bromo-pyridine-2-base amine 38 and 2-.
Scheme 10c
The preparation of step 1-(5-bromo-pyridine-2-base)-(the fluoro-benzyl of 2-)-amine (40):
In round-bottomed flask, 5-bromo-pyridine-2-base amine (38,4.05g, 23.4mmol) and the acetonitrile of 70.0mL, 2-are fluoro- Benzaldehyde (39,2.45mL, 23.4mmol), triethyl silicane (20.0mL, 125mmol) and trifluoroacetic acid (10.0mL, 130mmol) combine.Reaction is stirred 3 hours at 80 DEG C.Reactant is introduced in aqueous potassium carbonate and extracts by ethyl acetate Take.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column chromatography It is purified, the 20-60% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and under vacuo Remove solvent to provide desired compound (40,5.0g).
The preparation of step 2-6-(the fluoro-benzylamino of 2-)-pyridine-3-formaldehyde (41):
In round-bottomed flask, at-78 DEG C in nitrogen, (5-bromo-pyridine-2-base)-(the fluoro-benzyl of 2-)-amine (40, 3.90g, 13.9mmol) be incorporated in 5 minutes with the oxolane of 60.0mL knot in add tert-butyl lithium (5.57mL, in hexane 2.50M).After 30 minutes, in 5 minutes, other tert-butyl lithium (17.1mL, 1.7M in hexane) is added.After 25 minutes, Add DMF (2.6mL, 34mmol) and this mixture is stirred 70 minutes at-78 DEG C, then make it Warm to room temperature holding 1 hour.Reactant is introduced in aqueous ammonium chloride and is extracted with ethyl acetate.Organic moiety sulfur Acid sodium is dried, and filters and filtrate is concentrated under vacuum to provide desired compound (41,3.0g), and it is used for ensuing step Need not be further purified in Zhou.
The preparation of step 3-(the fluoro-benzyl of 2-)-(5-Formyl-pyridin-2-base)-t-butyl carbamate (42):
6-(the fluoro-benzylamino of 2-)-pyridine-3-formaldehyde (41,3.00g, 13.0mmol) in 57.2mL oxolane Middle addition Bis(tert-butoxycarbonyl)oxide (25,4.26g, 19.5mmol) and 4-dimethylaminopyridine (0.16g, 1.3mmol) and Triethylamine (3.6mL, 26mmol).Reaction is stirred at room temperature overnight, and is subsequently poured in water and is extracted with ethyl acetate.Organic portion Demultiplexing sodium sulfate is dried, and filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described 20-100% ethyl acetate eluting in silica gel column chromatography hexane.Suitably fraction is combined and removes solvent under vacuo To provide desired compound (41,3.50g).
Prepare other aldehyde being similar to the method for scheme 10c, as shown in following table, wherein step 1, step 2 and step 3 Reactant provides respectively in 1,2 and 3 row, and the aldehyde of the Boc protection obtained provides in the 4th row.The reaction condition side of being similar to Case 10c describe those, and for each step can slight variation, such as, as those skilled in the art are readily available, can Optional solvent, reactant, response time, temperature, shooting condition (work up condition) etc. is used to change solvent, anti- Answer any one in thing, response time, temperature, shooting condition or other response parameter.Such as, without limitation, for step 2, N-BuLi in the first time addition pentane of tert-butyl lithium or replaced by the isopropylmagnesium chloride in oxolane；For Step 3, triethylamine DIPEA replaces, or dichloromethane is used as solvent.Compound in following table passes through1H With13C NMR spectra and mass spectral characteristi.
As shown in scheme 10d, (the chloro-benzyl of 2-)-(6-fluoro-5-Formyl-pyridin-2-base)-t-butyl carbamate 48 prepare in four steps from the 6-chloro-benzaldehyde 44 of fluoro-pyridine-2-base amine 43 and 2-.
Scheme 10d
The preparation of step 1-(the chloro-benzyl of 2-)-(6-fluoro-pyridine-2-base)-amine (45):
6-fluoro-pyridine-2-base amine (43,2.47g, 22.0mmol) in 60.0mL acetonitrile adds the chloro-benzaldehyde of 2- (44,3.09g, 22.0mmol), triethyl silicane (14.0mL, 87.6mmol) and trifluoroacetic acid (7.00mL, 90.9mmol).Instead Should stir 4 hours at 80 DEG C, remove solvent the most under vacuo, and residue is combined with aqueous potassium carbonate and uses second Acetoacetic ester extracts.Organic layer saline washs, and is dried over sodium sulfate, filters and filtrate is concentrated under vacuum to provide expectation Compound, it need not be further purified in the lower step.MS(ESI)[M+H+]+=272.1.
The preparation of step 2-(the bromo-6-of 5-fluoro-pyridine-2-base)-(the chloro-benzyl of 2-)-amine (46):
At room temperature, (the chloro-benzyl of 2-) in 100.0mL acetonitrile-(6-fluoro-pyridine-2-base)-amine (45,4.70g, The N-bromosuccinimide (3.53g, 19.8mmol) 19.8mmol) being slowly added in 20.0mL acetonitrile.Reaction is at room temperature Stir 4 hours, be subsequently poured into aqueous potassium carbonate and be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters And filtrate is concentrated under vacuum.In the material hexane obtained ethyl acetate washing with provide desired compound (46, 5.0g)。
The preparation of step 3-6-(the chloro-benzylamino of 2-)-2-fluoro-pyridine-3-formaldehyde (47):
(5-bromo-6-fluoro-pyridine-2-in 10 minutes, in the 25.0mL oxolane at-78 DEG C in nitrogen Base)-(the chloro-benzyl of 2-)-amine (46,1.85g, 5.86mmol) addition isopropylmagnesium chloride (3.00mL, 2.00M in oxolane, 6.00mmol).After 50 minutes, in 5 minutes, tert-butyl lithium (7.80mL, 1.70M, 13.3mmol in hexane) is added.20 After minute, add DMF (1.09mL, 14.0mmol) and reactant mixture stirs 20 points at-78 DEG C Clock, then reached room temperature in 30 minutes.Reactant mixture is poured into water and is extracted with ethyl acetate.Organic layer salt is washed Wash, be dried over sodium sulfate, filter and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, 35% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and removes solvent under vacuo To provide desired compound (47,1.45g).MS(ESI)[M+H+]+=265.4.
The preparation of step 4-(the chloro-benzyl of 2-)-(6-fluoro-5-Formyl-pyridin-2-base)-t-butyl carbamate (48):
6-(the chloro-benzylamino of 2-)-2-fluoro-pyridine-3-formaldehyde in 31.4mL oxolane (47,1.45g, 5.48mmol) in add Bis(tert-butoxycarbonyl)oxide (25,1.79g, 8.22mmol) and 4-dimethylaminopyridine (78.6mg, 0.643mmol).Reaction is stirred at room temperature 3 hours, is then concentrated under vacuum.The material obtained passes through silica gel column chromatography It is purified, the 15-35% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and in vacuum Lower removal solvent is to be provided as the expectation compound (48,1.60g) of water white oil.
Prepare (the chloro-benzyl of 4-)-(6-fluoro-5-Formyl-pyridin-2-base)-amino first being similar to the method for scheme 10d Tert-butyl acrylate 52, first step changes into making 2 according to the following step 1a, and the chloro-benzylamine 50 of 6-Difluoro-pyridin 49 and 4-reacts.
Scheme 10d step 1a
The preparation of step 1-(the chloro-benzyl of 4-)-(6-fluoro-pyridine-2-base)-amine (51):
In 20.0mL N-Methyl pyrrolidone 2, add 4-in 6-Difluoro-pyridin (49,3.80g, 33.0mmol) Chloro-benzylamine (50,5.6mL, 46.0mmol) and DIPEA (10.0mL, 57.4mmol).Reaction is stirred at 90 DEG C Mix overnight, be subsequently poured in water and be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is in vacuum Lower concentration.The material obtained is purified by silica gel column chromatography, 25% ethyl acetate in described silica gel column chromatography hexane Eluting.Suitably fraction is combined and removes solvent under vacuo, and the material ethyl acetate/hexane washing obtained with It is provided as the expectation compound (51,5.30g) of white solid.
Its preparation in the step 1 of scheme 10d of 1b through the following steps, 3-methoxv-pyridine-2-base amine 54 (5-formoxyl-3-methoxv-pyridine-2-base)-(4-methyoxy-benzyl)-t-butyl carbamate 55 is from 3-methoxy Base-2-nitro-pyridine 53 is prepared in one step.Scheme 10d step 1b
The preparation of step 1-3-methoxv-pyridine-2-base amine (54):
3-methoxyl group-2-nitro-pyridine (53,7.00g, 45.4mmol) in 100mL methanol is degassed and adds palladium (0.7g, 20%).Under hydrogen capsule, reaction is stirred at room temperature one day.Reactant is filtered by kieselguhr and filtrate is in vacuum Lower concentration is to provide desired compound (54,5.555g).MS(ESI)[M+H+]+=125.3.
Prepare other aldehyde being similar to the method for scheme 10d, as shown in following table, wherein step 1 (or 1a), step 2, Step 3 and step 4 reactant provide respectively in 1,2,3 and 4 row, and the aldehyde of the Boc protection obtained provides in the 5th row.Step Rapid 1a uses and points out in the 1st row.Reaction condition is similar to those that scheme 10d describes, and can be somewhat for each step Change, such as, as those skilled in the art are readily available, can use optional solvent, reactant, response time, temperature, swash Clockwork spring parts etc. change any one in solvent, reactant, response time, temperature, shooting condition or other response parameter.Such as, Without limitation, for step 1a, do not use DIPEA；For step 3, the addition hexane of isopropylmagnesium chloride In n-BuLi replace；For step 4, reaction includes triethylamine and uses dichloromethane as solvent.Change in following table Compound passes through1H and13C NMR spectra and mass spectral characteristi.
(the bromo-6-of 5-fluoro-pyridine-2-base)-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate 56
Being prepared by the product of the step 2 of first entry from table, it is then with the method being similar to scheme 10d step 4 Carry out Boc protection.
As shown in scheme 10e, (6-fluoro-5-Formyl-pyridin-2-base)-(5-fluoro-6-methoxv-pyridine-3-Ji Jia Base)-t-butyl carbamate 61 is at four from 6-fluoro-pyridine-2-base amine 43 and 5-fluoro-6-methoxv-pyridine-3-formaldehyde 57 Preparation in step.
Scheme 10e
The preparation of step 1-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-(6-fluoro-pyridine-2-base)-amine (58):
6-fluoro-pyridine-2-base amine (43,1.50g, 13.4mmol) in 52.9mL acetonitrile adds 5-fluoro-6-methoxy Base-pyridine-3-formaldehyde (57,2.00g, 12.9mmol), triethyl silicane (10.6mL, 66.3mmol) and trifluoroacetic acid (5.3mL, 69.0mmol).Reaction is stirred overnight at 80 DEG C, is then concentrated under vacuum, is combined with water and uses ethyl acetate Extraction.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column layer Analysis is purified, the 15-100% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and very Empty lower concentration is with the expectation compound (58,3.21g) being provided as white solid.
The system of step 2-(the bromo-6-of 5-fluoro-pyridine-2-base)-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (59) Standby:
At room temperature, (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-(6-fluoro-pyridine-2-in 100mL acetonitrile Base)-amine (58,3.21g, 12.8mmol) is slowly added in 30mL acetonitrile N-bromosuccinimide (2.30g, 12.9mmol).Reaction is stirred at room temperature 4 hours, is subsequently poured in aqueous potassium carbonate and is extracted with ethyl acetate.Organic Layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, 20% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and is concentrated under vacuum to provide Desired compound (59,3.60g).
Step 3-(the bromo-6-of 5-fluoro-pyridine-2-base)-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-carbamic acid uncle The preparation of butyl ester (60):
(the bromo-6-of 5-fluoro-pyridine-2-base) in 58.7mL oxolane-(5-fluoro-6-methoxv-pyridine-3-Ji Jia Base)-amine (59,2.70g, 8.18mmol) adds Bis(tert-butoxycarbonyl)oxide (25,2.2g, 9.9mmol) and 4-dimethylamino Pyridine (0.29g, 2.4mmol).Reaction is stirred at room temperature 90 minutes, is then concentrated under vacuum.The material obtained passes through Silica gel column chromatography is purified, the 20-100% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is tied It is incorporated in reduced under vacuum to be provided as the expectation compound (60,3.0g) of water white oil.
Step 4-(6-fluoro-5-Formyl-pyridin-2-base)-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino first The preparation of tert-butyl acrylate (61):
(the bromo-6-of 5-fluoro-pyridine-2-base)-(fluoro-6-of 5-in the 25.0mL oxolane in nitrogen at-35 DEG C Methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (60,2.90g, 6.74mmol) middle addition isopropylmagnesium chloride (3.54mL, 2.00M, 7.08mmol in oxolane), then makes reaction reach 0 DEG C in 1 hour.Reaction is cooled to-45 DEG C and add DMF (1.0mL, 13.0mmol).Reaction was warmed to room temperature in 2 hours, is subsequently poured into and contains In the ammonium chloride of water and be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum. The material obtained is purified by silica gel column chromatography, 20% ethyl acetate eluting in described silica gel column chromatography hexane.Close Suitable fraction is combined and is concentrated under vacuum to provide desired compound (61,1.80g).
Prepare other aldehyde being similar to the method for scheme 10e, as shown in following table, wherein step 1, step 2, step 3 Thering is provided in 1,2,3 and 4 row respectively with step 4 reactant, the aldehyde of the Boc protection obtained provides in the 5th row.In some feelings In condition, it is desirable to compound be after the step 3 of following reaction separate Boc protection bromo compound.Reaction condition class Be similar to scheme 10e describe those, and for each step can slight variation, such as, as those skilled in the art easily obtain , when optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Between, any one in temperature, shooting condition or other response parameter.Such as, without limitation, nitrogen carries out step 2；Step 3 include DIPEA.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
With the method being similar to step 2-4 of step 1a of scheme 10d, then scheme 10e, from 2,6-Difluoro-pyridin 49 (S)-1-(4-fluoro-phenyl)-ethamine prepares (6-fluoro-5-Formyl-pyridin-2-base)-[(S)-1-(4-fluoro-phenyl)-second Base]-t-butyl carbamate 62
Step 3 also includes DIPEA, and is subsequently added Bis(tert-butoxycarbonyl)oxide and N, N-diisopropyl Ethamine.
With the method being similar to scheme 10e step 3 and 4, by reaction (5-iodo-6-methvl-pyridinium-2-base)-(6-methoxy Base-pyridin-3-yl methyl)-amine 65 prepares (5-formoxyl-6-methvl-pyridinium-2-base)-(6-methoxv-pyridine-3-Ji Jia Base)-t-butyl carbamate 66
Wherein step 3 includes DIPEA.As shown in scheme 10f, (5-iodo-6-methvl-pyridinium-2- Base)-(6-methoxv-pyridine-3-ylmethyl)-amine 65 is from 5-iodo-6-methvl-pyridinium-2-base amine 63 and 6-methoxyl group-pyrrole Pyridine-3-formaldehyde 64 is prepared in one step.
Scheme 10f
The preparation of step 1-(5-iodo-6-methvl-pyridinium-2-base)-(6-methoxv-pyridine-3-ylmethyl)-amine (65):
In round-bottomed flask, 5-iodo-6-methvl-pyridinium-2-base amine (63,1.7g, 7.3mmol) and 6-methoxv-pyridine- 3-formaldehyde (64,1.1g, 8.0mmol) and trifluoroacetic acid (2.80mL, 36.3mmol), triethyl silicane (5.80mL, 36.3mmol) combine with 50mL acetonitrile.This reaction is stirred at room temperature overnight, and then heats to reflux 6 hours.Reaction is in vacuum Lower concentration, is combined with aqueous carbonic acid potassium and is extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate It is concentrated under vacuum.The material obtained is purified by silica gel rapid column chromatography, in described silica gel rapid column chromatography hexane 10-100% ethyl acetate eluting.Suitably fraction combined and be concentrated under vacuum to provide desired compound (65, 1.80g)。MS(ESI)[M+H+]+=356.80.
Prepare other aldehyde being similar to the method for scheme 10f, then scheme 10e step 2 and 3, as shown in following table, its Middle step 1 (scheme 10f), step 3 and step 4 reactant provide respectively in 1,2 and 3 row, it is thus achieved that the aldehyde of Boc protection the 5 row provide.Reaction condition is similar to those that scheme 10e and 10f describe, and for each step can slight variation, example As, as those skilled in the art are readily available, optional solvent, reactant, response time, temperature, shooting condition can be used Deng any one changed in solvent, reactant, response time, temperature, shooting condition or other response parameter.
5-iodo-6-methvl-pyridinium-2-base amine 63 is substituted and with 5-fluoro-pyridine-3-formaldehyde with 5-iodo-pyrimidine-2-base amine Substitute 6-methoxv-pyridine-3-formaldehyde 64 and Boc-protection nitrogen such as according to the method similar with scheme 10e step 3, The scheme 10f of being similar to prepares (5-fluoro-pyridin-3-yl methyl)-(the iodo-pyrimidine-2-base of 5-)-t-butyl carbamate 67
As shown in scheme 10g, (5-formoxyl-pyrimidine-2-base)-(6-methoxv-pyridine-3-ylmethyl)-amino first Tert-butyl acrylate 72 is prepared three steps from vinamidinium salt 68 and guanidine hydrochloride 69.
Scheme 10g
The preparation of step 2-2-amidino-pyridine-5-formaldehyde (70):
Vinamidinium salt (68,158g, 413mmol) and guanidine hydrochloride (69,63.3g, 455mmol) are dissolved in Cool down in the acetonitrile of 527mL and in ice water bath.It is added dropwise over sodium hydroxide (66.1mL, 50%w/w, 827mmol), keeps Temperature is below 25 DEG C.Reaction is warmed to 25 DEG C and stirs 4 hours, then dilute with water filtering, from ethanol/heptane back extraction (strip), then develop with heptane.Be dried under vacuum obtained solid with provide desired compound (70,37g, 301mmol, 72.7% yield).
The preparation of step 2-2-[(6-methoxv-pyridine-3-ylmethyl)-amino]-pyrimidine-5-formaldehyde (71):
In round-bottomed flask, 2-amidino-pyridine-5-formaldehyde (70,0.750g, 6.09mmol), 6-methoxv-pyridine-3- Formaldehyde (64,1.67g, 12.2mmol), trifluoroacetic acid (2.5mL, 32.0mmol) and triethyl silicane (5.00mL, 31.3mmol) Be combined with 10mL acetonitrile.Reaction is at room temperature stirred overnight, and is then concentrated under vacuum and is combined also with aqueous potassium carbonate And be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained leads to Cross silica gel rapid column chromatography to be purified, the 15-100% ethyl acetate eluting in described silica gel rapid column chromatography hexane.Properly Fraction combined and be concentrated under vacuum to provide desired compound.
Step 3-(5-formoxyl-pyrimidine-2-base)-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (72) preparation:
2-[(6-methoxv-pyridine-3-ylmethyl)-amino]-pyrimidine-5-formaldehyde in 15mL oxolane (71, 0.462g, 1.89mmol) in add DIPEA (0.72mL, 4.2mmol), 4-dimethylaminopyridine (0.02g, 0.2mmol) and Bis(tert-butoxycarbonyl)oxide (25,0.45g, 2.1mmol).Reaction is stirred at room temperature overnight, and then falls Enter in water and be extracted with ethyl acetate.The material that organic layer is concentrated under vacuum and is obtained is pure by silica gel column chromatography Change, the 20-100% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and the denseest Contracting is to provide desired compound.1H NMR is consistent with compound structure.
Prepare other aldehyde being similar to the method for scheme 10g, as shown in following table, wherein step 1 and step 2 reactant Being respectively provided in 1 and 2 row, the aldehyde of the Boc protection obtained provides in arranging the 3rd.Reaction condition is similar to scheme 10g and describes Those, and for each step can slight variation, such as, as those skilled in the art are readily available, can use optional Solvent, reactant, response time, temperature, shooting condition etc. change solvent, reactant, response time, temperature, shooting condition Or any one in other response parameter.Such as, without limitation, for step 2, DIPEA is not included in reaction In.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
As shown in scheme 10h, (4-chloro-5-formyl thiazole-2-base)-(6-trifluoromethylpyridin-3-ylmethyl)- T-butyl carbamate 76 is from 2, and 4-bis-chloro-thiazole-5-formaldehyde 73 and C-(6-trifluoromethylpyridin-3-base)-methylamine 74 exists Preparation in two steps.
Scheme 10h
The preparation of the chloro-2-of step 1-4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-thiazole-5-formaldehyde (75):
At room temperature, to C-(6-trifluoromethylpyridin-3-base)-methylamine (74,1.0g, 5.7mmol) and N, N-diisopropyl Base ethamine (2.0mL, 11mmol) is added dropwise over 2 in 10mL oxolane in the solution of 100mL oxolane, and 4-bis-is chloro- Thiazole-5-formaldehyde (73,1.1g, 6.2mmol).Reactant mixture is stirred at room temperature overnight.Reactant mixture is introduced into frozen water In, it is extracted with ethyl acetate, washs with saline, be dried over sodium sulfate, filter and filtrate is concentrated under vacuum.Obtained Material is purified by silica gel column chromatography, the ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is tied It is incorporated in reduced under vacuum to provide desired compound (75,1.2g, 66%).MS (ESI)=[M+H+]+=322.11
Step 2-(4-chloro-5-formyl thiazole-2-base)-(6-trifluoromethylpyridin-3-ylmethyl)-carbamic acid uncle The preparation of butyl ester (76):
The chloro-2-of 4-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-thiazole-5-formaldehyde (75,1.2g, 3.7mmol), Bis(tert-butoxycarbonyl)oxide (25,0.98g, 4.5mol), 4-dimethylaminopyridine (0.09g, 0.7mmol) and N, N-diisopropylethylamine (0.96g, 7.5mmol) combines in the dichloromethane of 170mL and is stirred at room temperature overnight.Reaction is mixed Compound is introduced in frozen water, extracts with dichloromethane, washs with saline, is dried over sodium sulfate, filters and filtrate is in vacuum Lower concentration.The material obtained is purified by silica gel column chromatography, the ethyl acetate eluting in described silica gel column chromatography hexane. Suitably fraction is combined and is concentrated under vacuum to be provided as the expectation compound (76,1.5g, 95%) of yellow solid.
Prepare other aldehyde being similar to the method for scheme 10h, as shown in following table, wherein step 1 and step 2 reactant Being respectively provided in 1 and 2 row, the aldehyde of the Boc protection obtained provides in arranging the 3rd.Reaction condition is similar to scheme 10h and describes Those, and for each step can slight variation, such as, as those skilled in the art are readily available, can use optional Solvent, reactant, response time, temperature, shooting condition etc. change solvent, reactant, response time, temperature, shooting condition Or any one in other response parameter.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
As shown in scheme 10i, (6-fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl)-carbamic acid uncle Butyl ester 83 is from 2, and 6-Difluoro-pyridin 49 is prepared in six steps.
Scheme 10i
The preparation of step 1-(6-fluoro-pyridine-2-base)-(4-methyoxy-benzyl)-amine (78):
In 500mL N-Methyl pyrrolidone 2, add 4-methoxy in 6-Difluoro-pyridin (49,100g, 869mmol) Base-benzylamine (77,136mL, 1.043mol) and DIPEA (304mL, 1.738mol).Reaction is stirred at 90 DEG C Overnight, it is subsequently poured in 8L water.Precipitate is collected by filtration and washes with water, is then absorbed in ethyl acetate and uses Water washs.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material heptane obtained is developed And be collected by filtration to provide desired compound (78,151g, 650mmol, 74.8% yield).
The preparation of step 2-(the bromo-6-of 5-fluoro-pyridine-2-base)-(4-methyoxy-benzyl)-amine (79):
(6-fluoro-pyridine-2-base)-(4-methyoxy-benzyl)-amine in the 4L acetonitrile in nitrogen (78,151g, In 650mmol), it is dividedly in some parts N-bromosuccinimide (116g, 650mmol).After reaction 2 hours, remove under vacuo Solvent and in ethyl acetate absorb residue, be subsequently poured in aqueous sodium thiosulfate.Organic layer warm water washs, It is dried on sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is crystallized to provide desired chemical combination from heptane Thing (79,172g, 553mmol, 85% yield).
The preparation of the fluoro-6-of step 3-2-(4-Methoxy-benzylamino)-methyl nicotinate (80):
(the bromo-6-of 5-fluoro-pyridine-2-base)-(4-methyoxy-benzyl)-amine in 2L Paar flask, in 1.5L methanol (79,85g, 273mmol) adds triethylamine (77mL, 546mmol) and [1,1 '-bis-(diphenyl phosphine) ferrocene]) dichloro palladium] (II) (5.80g, 7.10mmol).Reaction is heated overnight at 100 DEG C under the carbon monoxide of 100psi.Reaction is cooled and leads to Cross kieselguhr filtration and filtrate is concentrated under vacuum.The material obtained is dissolved in dichloromethane and passes through silicagel column Plug, described silica gel plunger ethyl acetate eluting.Solvent is removed to be provided as the expectation compound of peachiness solid under vacuo (80,70g, 241mmol, 88% yield).
The preparation of step 4-[the fluoro-6-of 2-(4-Methoxy-benzylamino)-pyridin-3-yl]-methanol (81):
The fluoro-6-of 2-(4-Methoxy-benzylamino)-methyl nicotinate in 350mL oxolane (80,70g, It is added dropwise over lithium aluminium hydride reduction (362mL, 1M, 362mmol in oxolane) in 241mmol) to cool down simultaneously.Reaction is at room temperature stirred Mix 2 hours, be added dropwise over 14mL water, the aqueous NaOH of 14mL 15% and 42mL water the most in order, carry out cancellation.Add Enter methyl tertiary butyl ether(MTBE) (500mL) and remove solid by filtering.The solid that filtrate is concentrated under vacuum and is obtained is molten Solution is in dichloromethane, by silica gel plunger and with the 50-100% ethyl acetate eluting in heptane.Remove molten under vacuo Agent is to be provided as the expectation compound (81,63g, 240mmol, 100% yield) of pale solid.
The preparation of the fluoro-6-of step 5-2-(4-Methoxy-benzylamino)-pyridine-3-formaldehyde (82):
[the fluoro-6-of 2-(4-Methoxy-benzylamino)-pyridin-3-yl]-methanol in 1.25L ethyl acetate (81, 63g, 240mmol) middle addition manganese oxide (IV) (210g, 2.416mol).Reaction is stirred at room temperature overnight, and then passes through diatom Soil filters and kieselguhr ethyl acetate rinse.In conjunction with the filtrate solid heptane that is concentrated under vacuum and obtained grind Make and be collected by filtration, to be provided as the desired compound (82,62g, 238mmol, 99% yield) of white solid.
Step 6-(6-fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl)-t-butyl carbamate (83) Preparation:
In round-bottomed flask, in conjunction with the fluoro-6-of 2-(4-Methoxy-benzylamino)-pyridine-3-formaldehyde (82,62g, 238mmol), the tert-butyl alcohol of 600mL, Bis(tert-butoxycarbonyl)oxide (25,83mL, 357mmol) and dimethyl aminopyridine (2.91g, 23.82mmol).Reaction is stirred overnight at 30 DEG C and is then concentrated under vacuum.The material obtained passes through silica gel column layer Analysis is purified, the 0-20% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and in vacuum Lower removal solvent is to provide desired compound (83,54g, 150mmol, 62.9% yield).
As shown in scheme 10k, (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-(5-Formyl-pyridin-2-base)-ammonia Base t-butyl formate 94 is from 6-Amino-nicotinic acid methyl ester 90 and 5-fluoro-2-methoxv-pyridine-3-formaldehyde 37 in four steps Preparation.
Scheme 10k
The preparation of step 1-6-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-methyl nicotinate (91):
In round-bottomed flask, 6-Amino-nicotinic acid methyl ester (90,0.678g, 4.46mmol) and 5-fluoro-2-methoxv-pyridine- 3-formaldehyde (37,0.532g, 3.43mmol), 10.6mL acetonitrile, trifluoroacetic acid (1.32mL, 17.1mmol) and triethyl silicane (3.29mL, 20.6mol) combines.Reaction is heated to reflux 3 hours, is subsequently poured in water and is extracted with ethyl acetate.Organic layer Wash with saline, be dried over sodium sulfate, filter and filtrate is concentrated under vacuum.The material obtained passes through silica gel column chromatography It is purified, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction is combined and is concentrated under vacuum to carry For desired compound (91,832mg).MS(ESI)[M+H+]+=292.4.
Step 2-{6-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl } preparation of-methanol (92):
In nitrogen at-40 DEG C, 6-in 11mL oxolane [(5-fluoro-2-methoxv-pyridine-3-ylmethyl)- Amino]-methyl nicotinate (91,0.825g, 2.83mmol) middle addition tetrahydroxy lithium aluminate (5.66mL, 1.0M in oxolane, 5.66mmol).Make reaction warm to room temperature and be stirred overnight.Reactant is poured in aqueous 1M sodium hydroxide, then with containing The 1M hydrochloric acid of water neutralizes.Solid is leached by kieselguhr, kieselguhr ethyl acetate and oxolane washing.The water layer separated is used Ethyl acetate extraction and all organic layers are combined, wash with saline, are dried the most over sodium sulfate, filter and filtrate exists Reduced under vacuum.The material obtained is purified by silica gel column chromatography, silica gel column chromatography ethyl acetate and Hex.Close Suitable fraction is combined and is concentrated under vacuum to provide desired compound (92,357mg).MS(ESI)[M+H+]+= 264.4。
The preparation of step 3-6-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridine-3-formaldehyde (93):
To be dissolved in 8mL oxolane 6-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridine- 3-yl }-methanol (92,0.353g, 1.34mmol) middle addition Dai Si-Martin's high price iodine (Dess-Maritn periodinane) (0.626g, 1.47mmol) and reaction are stirred at room temperature 1 hour.Reactant is poured into containing water saturation sodium thiosulfite In (sodium thiosulfite) and aqueous layer with ethyl acetate extraction.In conjunction with organic layer with saline wash, at sodium sulfate Upper dry, filter and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described silica gel column layer Analysis ethyl acetate and Hex.Suitably fraction is combined and is concentrated under vacuum to provide desired compound.MS (ESI)[M+H+]+=262.3.
Step 4-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-(5-Formyl-pyridin-2-base) the tertiary fourth of-carbamic acid The preparation of ester (94):
To 6-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-the amino]-pyrrole being dissolved in 4.72mL oxolane Pyridine-3-formaldehyde (93,0.310g, 1.19mmol) adds 4-dimethylaminopyridine (14.5mg, 0.119mmol), adds subsequently Enter Bis(tert-butoxycarbonyl)oxide (25,0.285g, 1.30mmol).Reaction is stirred at room temperature overnight, and is then concentrated under vacuum.Institute The material obtained is purified by silica gel column chromatography, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction Combined and be concentrated under vacuum to provide desired compound (94,301mg).
With the method being similar to scheme 10k, replace the fluoro-2-of 5-with 5-fluoro-6-methoxv-pyridine-3-formaldehyde in step 1 Methoxv-pyridine-3-formaldehyde 37, preparation (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-(5-Formyl-pyridin-2-base)- T-butyl carbamate 95
To be similar to scheme 10k step 1-2 and the method for scheme 10i step 3, the most in step 1 by 5-amino-2-first Base-2H-pyrazoles-3-carboxylate methyl ester replace 6-Amino-nicotinic acid methyl ester 90 and with 3-chloro-benzaldehyde replacement 5-fluoro-2-methoxyl group- Pyridine-3-formaldehyde 37, prepares 5-(the chloro-benzylamino of 3-)-2-methyl-2H-pyrazoles-3-formaldehyde 96.
As shown in scheme 10n, 5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-formaldehyde 113 Being from 1H-pyrazoles-3,5-dicarboxylic acids is prepared in nine steps.
Scheme 10n
Step 1-1H-pyrazoles-3, the preparation of 5-dimethyl dicarboxylate (102):
In round-bottomed flask, 1H-pyrazoles-3,5-dicarboxylic acids hydrate (101,21.1g, 121mmol) ties with 350mL methanol Merge and add 10mL hydrochloric acid.Reaction is stirred overnight under reflux and next day stirs at room temperature.Reaction is concentrated under vacuum also And solid with ethyl acetate and hexane wash to provide desired compound.MS(ESI)[M+H+]+=185.
Step 2-1-(4-methyoxy-benzyl)-1H-pyrazoles-3, the preparation of 5-dimethyl dicarboxylate (104):
In round-bottomed flask, 1H-pyrazoles-3,5-dimethyl dicarboxylate (102,15.0g, 81.4mmol) and 1500mL acetone Combine with potassium carbonate (15g, 110mmol).Add 1-chloromethyl-4-methoxyl group-benzene (103,10.0mL, 73.8mmol) and anti- Should be stirred overnight at 60 DEG C.Mixture it is divided in two flasks and continues to stir 5 hours.Reaction be concentrated under vacuum and Solid cold water washs and is dried under vacuum to provide desired compound (104,20.48g).1H NMR and compound structure Unanimously.
Step 3-1-(4-methyoxy-benzyl)-1H-pyrazoles-3, the preparation of 5-dicarboxylic acids 5-methyl ester (105):
In round-bottomed flask, 1-(4-methyoxy-benzyl)-1H-pyrazoles-3,5-dimethyl dicarboxylate (104,28.5g, 93.6mmol) with 100mL water and 20mL Isosorbide-5-Nitrae-twoAlkane combines.Add sulphuric acid (5.5mL, 100mm0l) and 2.0mL water and Reaction is stirred 2 days at 60-70 DEG C.Reaction is concentrated under vacuum until precipitating formation.Solid by filtration is collected and uses cold water Washing is several times to provide desired compound.1H NMR is consistent with compound structure.
The preparation of step 4-5-azidocarbonyl-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (106):
In round-bottomed flask, 1-(4-methyoxy-benzyl)-1H-pyrazoles-3,5-dicarboxylic acids 5-methyl ester (105,5.48g, 18.9mmol) combine with 20mL toluene and thionyl chloride (6mL, 80mmol).Reaction heating 40 minutes under reflux, then by first The solid that benzene concentrates twice and obtained is dried under vacuum.This reactant is dissolved in the acetone of 30.0mL and adds Hydrazoic acid,sodium salt (3.8g, 58mmol) in 10.0mL water also stirs 1 minute.Reactant is poured in the frozen water of 250mL and slowly Stirring.The precipitate obtained is collected by filtration and is dried under vacuum to provide desired compound.
The preparation of step 5-5-benzyloxy carbonyl amino-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (108):
In round-bottomed flask, 5-azidocarbonyl-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (106, 5.6g, 18.0mmol) be combined and add benzylalcohol (107,1.91mL, 18.5mmol) with the toluene of 30mL and react under reflux Heat 1 hour.The material methanol that reaction is concentrated under vacuum and is obtained washs 2 times to be provided as the expectation of white solid Compound.1H NMR is consistent with compound structure.
The preparation of step 6-5-amino-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (109):
In round-bottomed flask, 5-benzyloxy carbonyl amino-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylic acid in nitrogen Methyl ester (108,2.3g, 5.8mmol) is combined with the methanol of 30mL and the oxolane of 10mL and adds the palladium on carbon of 10% (0.23g, 13.0mmol).Reaction is stirred 2 hours in hydrogen under 1 atmospheric pressure.Reactant filtered and filtrate under vacuo Concentrate to provide desired compound (109,1.4g).
The system of step 7-5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (111) Standby:
In round-bottomed flask, 5-amino-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (109,1.4g, 5.4mmol) with the fluoro-benzaldehyde of 4-(110,0.565mL, 5.36mmol), trifluoroacetic acid (2.06mL, 26.8mmol), triethyl group Silane (4.28mL, 26.8mmol) and 50mL acetonitrile combine.Reaction is stirred at room temperature 15 minutes, is then concentrated under vacuum, Be combined with aqueous potassium carbonate and be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is very Empty lower concentration.The mixture recrystallization of residue from ethyl acetate and hexane is to provide desired compound (111,1.6g).1H NMR is consistent with compound structure.
Step 8-[5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazole-3-yl]-methanol (112) Preparation:
In round-bottomed flask, 5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-carboxylate methyl ester (111,1.6g, 4.3mmol) is combined with 100mL oxolane and is cooled to-40 DEG C.Addition tetrahydroxy lithium aluminate (4.8mL, four 1.0M, 4.8mmol in hydrogen furan) and reaction is warmed to 10 DEG C.Reaction sodium sulfate decahydrate cancellation, then stirring 2 is little Time, filtered by kieselguhr and filtrate is concentrated under vacuum.The material ethyl acetate obtained and hexane wash and are dried Solid is to provide desired compound.MS(ESI)[M+H+]+=342.30.
The preparation of step 9-5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-formaldehyde (113):
In round-bottomed flask, [5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-in nitrogen Base]-methanol (112,1.6g, 4.2mmol) and 300mL dichloromethane and manganese oxide (IV) (0.61g, 7.0mmol) combine and stir Mix overnight.Reactant is filtered by kieselguhr and filtrate is concentrated under vacuum.The material obtained is pure by silica gel column chromatography Change, the 10-100% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and the denseest Contract to provide desired compound (113,1.4g).1H NMR is consistent with compound structure.
Embodiment 11:(6-bromo-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base] synthesis of-amine P-2002.
As shown in scheme 11, (6-bromo-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine P-2002 is to prepare in five steps from 5-chloro-1H-pyrrolo-[2,3-b] pyridine 1.
Scheme 11
The preparation of step 1-5-chloro-1H-pyrrolo-[2,3-b] pyridine-3-formaldehyde (114):
In round-bottomed flask, 5-chloro-1H-pyrrolo-[2,3-b] pyridine (1,10.0g, 65.5mmol) and hexa-methylene four Amine (11.9g, 85.2mmol), acetic acid (28.3mL, 0.498mol) and 56.7mL water combine.Reactant is the most heated At night, it is subsequently adding 200mL water.After 30 minutes, solid matter is collected by filtration and is dried to provide desired compound (114,7.0g).
The preparation of step 2-1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridine-3-formaldehyde (115):
5-chloro-1H-pyrrolo-[2,3-b] pyridine-3-formaldehyde in 100mL dichloromethane (114,3.60g, Potassium hydroxide (50mL, 9M aqueous solution, 0.45mol), 4-butyl ammonium hydrogen sulfate (400mg, 1.0mmol) is added in 19.9mmol) With benzene sulfonyl chloride (11,2.9mL, 23.0mmol).Reaction is stirred at room temperature 3 hours, is subsequently poured in water and uses ethyl acetate Extraction.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material ethyl acetate obtained is washed Wash to be provided as the expectation compound (115,2.3g) of white solid.
Step 3-(1-benzenesulfonyl 5-chlorine 1H-pyrrolo-[2,3-b] pyridin-3-yl)-[6-(2,2,5,5-tetramethyls- [1,2,5] azepine disilane-1-base)-pyridin-3-yl]-methanol (118) and (6-amino-pyridine-3-base)-(1-benzenesulfonyl- 5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl) preparation of-methanol (119):
In round-bottomed flask, in nitrogen at-78 DEG C, 2-amino-5-bromopyridine (116,3.10g, 17.9mmol) with 80.0mL oxolane combines, and is slowly added into n-BuLi (7.10mL, 2.50M, 17.8mmol in hexane).After 30 minutes, It is slowly added into 1 in 20mL oxolane, 2-pair-(chloro-dimethyl-silane base)-ethane (117,3.90g, 18.1mmol), and And make reaction reach room temperature in one hour.Reaction be cooled to-78 DEG C and add other n-BuLi (7.10mL, oneself 2.50M in alkane, 17.8mmol).Reaction is stirred 30 minutes at-78 DEG C and makes it warm to room temperature in one hour.Reaction It is cooled to-78 DEG C and is slowly added into other n-BuLi (7.50mL, 2.50M, 18.8mmol in hexane).After 1 hour, add 1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridine-3-formaldehyde in 30mL oxolane (115,1.90g, 5.92mmol) and react stirring 2 hours at-78 DEG C, then make it warm to room temperature in 1 hour.Reactant pours water into In, it is extracted with ethyl acetate and organic layer is dried over sodium sulfate, filter and filtrate is concentrated under vacuum.Obtained Material is purified by silica gel column chromatography, and the 2-20% methanol-eluted fractions in described silica gel column chromatography dichloromethane is to provide chemical combination Thing (118,1.7g) and the mixture of (119,1.25g).MS (the ESI) [M+H of 118+]+MS (the ESI) [M-H of=554.4 and 119+]-=415.2.
Step 4-5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine (120) preparation:
(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl)-[6-in 25.0mL dichloromethane (2,2,5,5-tetramethyls-[1,2,5] azepine disilane-1-base)-pyridin-3-yl]-methanol and (6-amino-pyridine-3-base)- (1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl)-methanol (118,119,1.70/1.25g mixture, Addition triethyl silicane (3.00mL, 18.8mmol) and trifluoroacetic acid (1.50mL, 19.5mmol) in 2.41mmol), and instead Should be stirred at room temperature overnight.Reaction is concentrated under vacuum, and is combined with aqueous potassium carbonate and is extracted with ethyl acetate.Organic Layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, 20-100% ethyl acetate eluting in described silica gel column chromatography hexane is to provide desired compound (120,0.70g).
Step 5-(6-bromo-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base] preparation of-amine (P-2002):
5-in 2.00mL ethanol and 0.10mL acetic acid (1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl) in-pyridine-2-base amine (120,80.0mg, 0.200mmol), add 6-bromo-pyridine-3-formaldehyde (121, 100.0mg, 0.538mmol) and silicon dioxide carried Cyanoborohydride (0.50g, 1.21mmol/g).Reaction is in microwave Heat 25 minutes at 110 DEG C.Add sodium hydroxide (2.0mL, 6.0M aqueous solution) and react and add at 100 DEG C in microwave Heat 10 minutes, is subsequently poured in aqueous ammonium chloride and is extracted with ethyl acetate.Organic layer is separated, and does over sodium sulfate Dry, filter and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, and described silica gel column chromatography is used 20% ethyl acetate washing in hexane.Suitably fraction is combined and solvent goes under vacuo divided by providing desired chemical combination Thing (P-2002,26.6mg).MS(ESI)[M+H+]+=427.7,429.7.
With the method being similar to scheme 11, replace 6-with 6-chloro-pyridine-3-formaldehyde and 6-fluoro-pyridine-3-formaldehyde respectively Bromo-pyridine-3-formaldehyde 121, prepares (6-chloro-pyridin-3-yl methyl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine P-2003 and [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(the fluoro-pyridine of 6---ylmethyl)-amine P-2004
MS(ESI)[M+H+]+=383.9,385.9 (P-2003) and 367.9,368.9 (P-2004).
Embodiment 12:[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2,6-diformazans Epoxide-pyridin-3-yl methyl) synthesis of-amine P-1496.
As shown in scheme 12, [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2, 6-dimethoxy-pyridin-3-ylmethyl)-amine P-1496 is from 5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base amine 120 and 2,6-dimethoxy-pyridin-3-formaldehyde 121 is prepared in two steps.
Scheme 12
Step 1-[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-also [2,3-b] pyridin-3-yl methyl)-pyridine-2- Base] preparation of-(2,6-dimethoxy-pyridine-3-ylmethyl)-amine (122):
5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridine-3-in 2.0mL ethanol and 0.1mL acetic acid Ylmethyl) in-pyridine-2-base amine (120,60.0mg, 0.150mmol), add 2,6-dimethoxy-pyridin-3-formaldehyde (121, 120mg, 0.75mmol) and silicon dioxide carried Cyanoborohydride (0.40g, 0.484mmol).Reaction in microwave It is heated to 100 DEG C under 300 watts and continues 18 minutes, be subsequently poured in aqueous potassium carbonate and be extracted with ethyl acetate.Organic Layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, 20% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and is concentrated under vacuum to provide Desired compound (122,60mg).
Step 2-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2,6-dimethoxies Base-pyridin-3-yl methyl) preparation of-amine (P-1496):
[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole in 10.0mL methanol Pyridine-2-base]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (122,60mg, 0.11mmol) middle addition potassium hydroxide (0.20g, 3.6mmol).Reaction is stirred 4 hours at 60 DEG C, is subsequently poured in water and is extracted with ethyl acetate.Organic layer is at sulfur It is dried on acid sodium, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described silicon 20-100% ethyl acetate eluting in plastic column chromatography hexane.Suitably fraction is combined and is concentrated under vacuum to provide the phase The compound (P-1496,26.1mg) hoped.MS(ESI)[M+H+]+=410.0.
Preparing other compound according to the method for scheme 12, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.Such as, without limitation, 4-butyl ammonium fluoride trihydrate For replacing the potassium hydroxide in step 2.Optionally with suitable aldehyde replace 2,6-dimethoxy-pyridin-3-formaldehyde 121 and Optionally replace 5-(the chloro-1H-of 1-benzenesulfonyl-5-with 1H-pyrrolo-[2, the 3-b)] pyridine of suitable 1-benzenesulfonyl protection Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine 120, prepare compound.This process is used to prepare following chemical combination Thing.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
(6-chloro-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1498), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-amine (P-1502), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1503), [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1504) and [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1505).
Following table shows in step 1 to provide the 1H-pyrroles of the 1-benzenesulfonyl protection of expectation compound (the 4th row) And [2,3-b] pyridine (the 2nd row) and aldehyde compound (the 3rd arranges).Compound number provides in arranging the 1st, and the matter observed Measure in arranging the 5th.
Embodiment 13:(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base] synthesis of-amine P-1599.
As shown in scheme 13, (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine P-1599 is from 1-benzenesulfonyl-3-iodo-5-methoxyl group-1H-pyrroles And [2,3-b] pyridine 16 and (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-(5-formoxyl-pyrimidine-2-base)-carbamic acid The tert-butyl ester 123 is prepared in three steps.
Scheme 13
Step 1-{5-[(1-benzenesulfonyl-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxy-methyl]- Pyrimidine-2-base } preparation of-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (124):
1-benzenesulfonyl-3-iodo-5-methoxyl group-1H-pyrrolo-[2,3-at-50 DEG C, in 4.0mL oxolane B] pyridine (16,1 equivalent) solution is slowly added into isopropylmagnesium chloride (2.0M, 1 equivalent in oxolane).To react at 70 points It is warmed to 5 DEG C in clock, is subsequently cooled to-45 DEG C and (the 5-fluoro-2-methoxv-pyridine-3-base adding in 2.0mL oxolane Methyl)-(5-formoxyl-pyrimidine-2-base)-t-butyl carbamate (123,0.78 equivalent).Reaction was warmed in 1 hour Room temperature, is subsequently poured in aqueous ammonium chloride and extracts with ether.Organic layer is dried over sodium sulfate, filters and filtrate exists Reduced under vacuum.The material obtained passes through silica gel column chromatography purification, the 20-100% second in described silica gel column chromatography hexane Acetoacetic ester eluting.The fraction being suitable for is combined and is concentrated under vacuum to provide desired compound.
Step 2-[5-(1-benzenesulfonyl-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base] preparation of-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (125):
5-in 10.0mL acetonitrile [(1-benzenesulfonyl-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl)- Hydroxy-methyl]-pyrimidine-2-base }-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (124,1 equivalent) Middle addition triethyl silicane (15.6 equivalent) and trifluoroacetic acid (16.9 equivalent).Reaction is heated 2 hours at 80 DEG C, is subsequently poured into In aqueous potassium carbonate and be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is the denseest Contracting is to provide desired compound, and it need not be further purified in following step.
Step 3-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyrimidine-2-base] preparation of-amine (P-1599):
[5-(1-benzenesulfonyl-5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl in 15.0mL oxolane Methyl)-pyrimidine-2-base] the middle addition tetrabutyl fluorination of-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (125,1 equivalent) Ammonium trihydrate (2 equivalent).Reaction is stirred at room temperature overnight, and is subsequently poured in water and is extracted with ethyl acetate.Organic layer exists It is dried on sodium sulfate, filters and filtrate is concentrated under vacuum.Obtained material passes through silica gel column chromatography purification, described silicagel column 20-100% ethyl acetate eluting in chromatography hexane.The fraction being suitable for is combined and is concentrated under vacuum to be provided as yellow The expectation compound of solid.
Preparing other compound according to the method for scheme 13, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.In step 1, the aldehyde generation that applicable Boc protects is used For (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-(5-formoxyl-pyrimidine-2-base)-t-butyl carbamate 123, preparationization Compound.This process is used to prepare following compounds.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-amine (P-1600), (5-fluoro-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1601), (6-chloro-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1602), [5-(5-methoxyl group-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1603), (6-methoxyl group- Pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P- 1604), [5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethyl-pyrrole Pyridine-3-ylmethyl)-amine (P-1605), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1606), 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) first Base] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl] pyridine-2-amine (P-2203) and 3-[[2-fluoro-6-[(5- Fluoro-6-methoxyl group-3-pyridine radicals) methylamino]-3-pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P- 2204)。
Following table shows in step 1 to provide the aldehyde compound (the 2nd row) of expectation compound (the 3rd row).Compound During numbering provides in arranging the 1st, and the quality observed arranges the 4th.
Embodiment 14:(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base] synthesis of-amine P-1547.
As shown in scheme 14, (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[3-methoxyl group-5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine P-1547 is from (5-formoxyl-3-methoxv-pyridine-2- Base)-(4-methyoxy-benzyl)-t-butyl carbamate 55 and 5-methyl isophthalic acid H-[2,3-b] pyridine 126 makes in three steps Standby.
Scheme 14
Step 1-{5-[hydroxyl-(5-methyl 1H-pyrrolo-[2,3-b] pyridin-3-yl)-methyl]-3-methoxv-pyridine- 2-yl }-the preparation of (4-methyoxy-benzyl)-t-butyl carbamate (127):
In phial, 5-methyl isophthalic acid H-[2,3-b] pyridine (126,1 equivalent) with (5-formoxyl-3-methoxv-pyridine- 2-yl)-(4-methyoxy-benzyl)-t-butyl carbamate (55,1.1 equivalent), 5mL methanol and potassium hydroxide (3 equivalent) knot Close.Reaction is stirred at room temperature overnight, and is subsequently adding aqueous 1N hydrochloric acid and mixture is extracted with ethyl acetate.Organic layer is used Water, saline wash, and are dried the most over magnesium sulfate, filter and filtrate is concentrated under vacuum.Obtained material passes through silicagel column Chromatography purification, described silica gel column chromatography methanol and dichloromethane eluent.Suitably fraction combined and be concentrated under vacuum with Desired compound is provided.
Step 2-3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine (128) preparation:
In round-bottomed flask, { 5-[hydroxyl-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl)-methyl]-3-methoxy Base-pyridine-2-base }-(4-methyoxy-benzyl)-t-butyl carbamate (127,1 equivalent) and 100mL acetonitrile, triethyl silicane (18 equivalent) and trifluoroacetic acid (18 equivalent) combine.Reaction is heated 24 hours under reflux, is then concentrated under vacuum.Obtained The material obtained is dissolved in 40mL trifluoroacetic acid and is stirred at room temperature 18 hours.This reactant be concentrated under vacuum and with water and Sodium bicarbonate combines, and is then extracted with ethyl acetate.Organic layer sodium bicarbonate, water, saline wash, and then do with magnesium sulfate Dry, filter and filtrate is concentrated under vacuum.Obtained material passes through silica gel column chromatography purification, described silica gel column chromatography acetic acid Ethyl ester and Hex.The fraction being suitable for is combined and is concentrated under vacuum to provide desired compound.
Step 3-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base] preparation of-amine (P-1547):
3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine in 2mL acetonitrile- 2-base amine (128,1 equivalent) adds 5-fluoro-2-methoxv-pyridine-3-formaldehyde (37,1 equivalent), triethyl silicane (5 equivalent) With trifluoroacetic acid (6.9 equivalent).Reaction at 80 DEG C heated 18 hours, be then concentrated under vacuum and with aqueous potassium carbonate Mix and be extracted with ethyl acetate.Organic layer use water, saline wash, and are dried the most over magnesium sulfate, filter and filtrate exists Reduced under vacuum.Obtained material passes through silica gel column chromatography purification, described silica gel column chromatography ethyl acetate and Hex.Suitable The fraction closed is combined and is concentrated under vacuum to provide desired compound.
Preparing other compound according to the method for scheme 14, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.In step 3, applicable aldehyde is used to replace the fluoro-2-of 5- Methoxv-pyridine-3-formaldehyde 37, prepares compound.This process is used to prepare following compounds.Compound in following table passes through1H With13C NMR spectra and mass spectral characteristi.
(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-amine (P-1548), (5-fluoro-pyridin-3-yl methyl)-[3-methoxyl group-5-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1549), (6-chloro-pyridin-3-yl methyl)-[3- Methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1550), [3-methoxy Base-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-base Methyl)-amine (P-1551), [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1552) and [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1553).
Following table shows in step 3 to provide the aldehyde compound (the 2nd row) of expectation compound (the 3rd row).Compound During numbering provides in arranging the 1st, and the quality observed arranges the 4th.
Embodiment 15:[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-[(S)-1- (4-fluoro-phenyl)-ethyl] synthesis of-amine P-2005.
As shown in scheme 15, [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]- [(S)-1-(4-fluoro-phenyl)-ethyl]-amine P-2005 is from the chloro-3-of 1-benzenesulfonyl-5-iodo-1H-pyrrolo-[2,3-b] pyrrole Pyridine 12 and 2-methylsulfanyl pyrimidin-5-formaldehyde 129 is prepared in 4 steps.
Scheme 15
Step 1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl)-(2-methylsulfanyl pyrimidin- 5-yl) preparation of-methanol (130):
The chloro-3-of 1-benzenesulfonyl-5-iodo-1H-pyrrolo-in the 96.3mL oxolane at-40 DEG C in nitrogen (10.1mL, in oxolane to be slowly added into isopropylmagnesium chloride in [2,3-b] pyridine (12,8.40g, 20.1mmol) solution 2.0M, 20.3mmol).Reaction is heated to 5 DEG C in 60 minutes, is subsequently cooled to-40 DEG C, be subsequently added 15.0mL tetrahydrochysene furan 2-methylsulfanyl pyrimidin-5-formaldehyde (129,2.50g, 16.2mmol) in muttering.Reaction was warmed to 10 DEG C in 2 hours, It is subsequently poured in aqueous ammonium chloride and is extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate It is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, the 40-in described silica gel column chromatography hexane 100% ethyl acetate eluting.Suitably fraction is combined and removes solvent under vacuo to be provided as the expectation of pale solid Compound (130,4.0g).MS(ESI)[M+H+]+=447.2.
The chloro-3-of step 2-1-benzenesulfonyl-5-(2-methylsulfanyl pyrimidin-5-ylmethyl)-1H-pyrrolo-[2,3-b] The preparation of pyridine (131):
(1-benzenesulfonyl-5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl)-(2-methyl in 120.0mL acetonitrile Sulfanyl-pyrimidine-5-base)-methanol (130,4.70g, 10.5mmol) adds triethyl silicane (22.0mL, 138mmol) and Trifluoroacetic acid (11.0mL, 143mmol).Reaction at 80 DEG C stir 3 hours, be then concentrated under vacuum and with aqueous carbonic acid Potassium mixes and is extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.Obtained The material obtained is by silica gel column chromatography purification, the 20-100% ethyl acetate eluting in described silica gel column chromatography hexane.Properly Fraction combined and under vacuo remove solvent with provide desired compound (131,2.90g).
The chloro-3-of step 3-1-benzenesulfonyl-5-(2-methanesulphonyl-pyrimidine-5-ylmethyl)-1H-pyrrolo-[2,3-b] pyrrole The preparation of pyridine (132):
The 1-chloro-3-of benzenesulfonyl-5-(2-methylsulfanyl pyrimidin-5-at 0 DEG C, in 100.0mL dichloromethane Ylmethyl)-1H-pyrrolo-[2,3-b] pyridine (131,4.40g, 10.2mmol) middle addition metachloroperbenzoic acid (maximum 77%, 4.90g, 21.9mmol).Reaction is stirred 40 minutes at 0 DEG C, is subsequently poured in water and is extracted with ethyl acetate.Organic Layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, 20% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction combined and remove under vacuo solvent with Desired compound (132,3.76g) is provided.MS(ESI)[M+H+]+=463.0.
Step 4-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-[(S)-1-(4- Fluoro-phenyl)-ethyl] preparation of-amine (P-2005):
In microwave phial, the chloro-3-of 1-benzenesulfonyl-5-(2-methanesulphonyl-pyrimidine-5-ylmethyl)-1H-pyrrolo- [2,3-b] pyridine (132,12mg, 0.026mmol) and 600 μ LN-methyl pyrrolidones and (S)-1-(4-fluoro-phenyl)-ethamine (133,25.2mg, 0.18mmol) mixes.Reaction is radiated 40 minutes in microwave at 200 DEG C, is subsequently adding potassium hydroxide (500 μ L, 4.00M in water) and react in microwave at 90 DEG C by radiation 10 minutes.Reaction is by adding in 120 μ L acetic acid With, solvent is removed under vacuo, and the material obtained is dissolved in 400 μ L dimethyl sulfoxide with by HPLC purification. Desired compound is purified on Phenomenex C18 post (50mm × 10mm ID), and described post has 0.1% trifluoro in water The Mobile phase B of 0.1% trifluoroacetic acid in the mobile phase A of acetic acid, acetonitrile, moved 20-under the flow velocity of 6mL/min in 16 minutes 100%B.The fraction being suitable for is collected and removes under vacuo solvent to provide desired compound.MS(ESI)[M+H+]+= 381.9。
According to the method for scheme 15 step 1-3, in step 1 with the fluoro-3-of 1-benzenesulfonyl-5-iodo-1H-pyrrolo-[2, 3-b] pyridine or 1-benzenesulfonyl-3-iodo-5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine replace the 1-chloro-3-of benzenesulfonyl-5- Iodo-1H-pyrrolo-[2,3-b] pyridine 12, prepares the 1-fluoro-3-of benzenesulfonyl-5-(2-methanesulphonyl-pyrimidine-5-the most respectively Ylmethyl)-1H-pyrrolo-[2,3-b] pyridine 134 and 1-benzenesulfonyl-3-(2-methanesulphonyl-pyrimidine-5-ylmethyl)-5-first Base-1H-pyrrolo-[2,3-b] pyridine 135
Use these to prepare other compound according to the method for scheme 15 step 4.For the substituted compound of 5-fluorine Certain situation in, benzenesulfonyl blocking group remove by reacting with the 4-butyl ammonium fluoride trihydrate in oxolane Other step completes.
Preparing other compound according to the method for scheme 15 step 4, its conditional alterable, such as, such as art technology Personnel are readily available, and optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reaction Any one in thing, response time, temperature, shooting condition or other response parameter.(4-is fluoro-to replace (S)-1-with suitable amine Phenyl)-ethamine 133 and with the 1-fluoro-3-of benzenesulfonyl-5-(2-methanesulphonyl-pyrimidine-5-ylmethyl)-1H-pyrrolo-[2, 3-b] pyridine 134 or 1-benzenesulfonyl-3-(2-methanesulphonyl-pyrimidine-5-ylmethyl)-5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridine 135 optionally replaces the 1-chloro-3-of benzenesulfonyl-5-(2-methanesulphonyl-pyrimidine-5-ylmethyl)-1H-pyrrolo-[2,3-b] Pyridine 132, prepares compound.This process is used to prepare following compounds.Compound in following table passes through1H and13C NMR spectra And mass spectral characteristi.
(3-chloro-4-Methyl-benzvl)-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-2007), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(3,4-bis-is fluoro- Benzyl)-amine (P-2008), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(fluoro-5-of 3- Romethyl-benzy)-amine (P-2009), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]- (3-trifluoromethoxy-benzyl)-amine (P-2010), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-(3-fluoro-4-romethyl-benzy)-amine (P-2011), (the chloro-benzyl of 4-)-[5-(5-chloro-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-methyl-amine (P-2012), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-(3-Methyl-benzvl)-amine (P-2013), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2-base]-(3-fluoro-4-Methyl-benzvl)-amine (P-2014), [2-(the chloro-phenyl of 3-)-ethyl]-[(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2015), [2-(the chloro-phenyl of 2-)-ethyl]-[5- (5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2020), [5-(5-chloro-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-[2-(4-fluoro-phenyl)-ethyl]-amine (P-2021), [5-(the chloro-1H-of 5- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-[2-(6-methvl-pyridinium-2-base)-ethyl]-amine (P- 2022), butyl-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2026), [5- (5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(1-thiazol-2-yl-ethyl)-amine (P- 2039), [1-(4-fluoro-phenyl)-propyl group]-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-2053), [1-(4-fluoro-phenyl)-cyclopropyl]-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-amine (P-2055), [(S)-1-(4-fluoro-phenyl)-ethyl]-[5-(5-fluoro-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2056), (2-methoxv-pyridine-4-ylmethyl)-[5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2069), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyrimidine-2-base]-(2-methoxv-pyridine-4-ylmethyl)-amine (P-2074), [5-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-pyridine-2-ylmethyl-amine (P-2076), [5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-pyridin-3-yl methyl-amine (P-2077), (6-chloro-pyridine-3- Ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2078), (6-first Base-pyridine-2-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P- 2079), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethylpyridin- 3-ylmethyl)-amine (P-2080), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6- Morpholine-4-base-pyridine-2-ylmethyl)-amine (P-2081), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-(6-pyrrolidin-1-yl-pyridine-2-ylmethyl)-amine (P-2082), (5-EthylPyridine-2-Ji Jia Base)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2083), (3-methyl- Pyridin-4-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P- 2084), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(2-morpholine-4-base-pyridine- 4-ylmethyl)-amine (P-2085), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-pyrrole Pyridine-4-ylmethyl-amine (P-2138), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyrimidine-2-base]-amine (P-2139), [6-(4-thyl-piperazin-1-base)-pyridin-3-yl methyl]-[5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2140), (2-methvl-pyridinium-4- Ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2141), (2-second Epoxide-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2142), (2-cyclopentyloxy-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-amine (P-2148) and (2-cyclopentyloxy-pyridin-4-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2149).
Following table shows in step 4 to provide 1H-pyrrolo-[2, the 3-b] pyridine (the of expectation compound (the 4th row) 2 row) and amines (the 3rd row).During compound number provides in arranging the 1st, and the quality observed arranges the 5th.
Embodiment 16:(5-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base Amino]-methyl }-pyrimidine-2-base) synthesis of-methyl-amine P-2095.
As shown in scheme 16, (5-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base amino]-methyl-pyrimidine-2-base)-methyl-amine P-2095 be from 3-iodo-5-methyl isophthalic acid-tri isopropyl silane base- 1H-pyrrolo-[2,3-b] pyridine 9 and (6-fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl) tertiary fourth of-carbamic acid Ester 83 is prepared in three steps.
Scheme 16
The fluoro-5-of step 1-{6-[hydroxyl-(5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine-3- Base)-methyl]-pyridine-2-base }-the preparation of (4-methyoxy-benzyl)-t-butyl carbamate (136):
3-iodo-5-methyl isophthalic acid-tri isopropyl silane base in the 400mL oxolane at-20 DEG C in nitrogen- 1H-pyrrolo-[2,3-b] pyridine (9,40g, 97.0mmol) middle addition isopropylmagnesium chloride (54.8mL, 2M in oxolane, 110mmol) and by reaction in 30 minutes, it is warmed to 0 DEG C.Reaction is cooled to-40 DEG C and the (6-adding in oxolane Fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl)-t-butyl carbamate (83,15.81g, 43.9mmol).Will Reaction was warmed to 0 DEG C in 1 hour, then with saline cancellation and be extracted with ethyl acetate.Organic layer is done over sodium sulfate Dry, filter and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, and described silica gel column chromatography is used 0-40% ethyl acetate eluting in hexane.Suitably fraction is combined and removes solvent under vacuo to provide desired chemical combination Thing (136,21g, 32.4mmol, 73.8% yield).
The fluoro-5-of step 2-6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine (137) Preparation:
{ the fluoro-5-of 6-[hydroxyl-(5-methyl isophthalic acid-tri isopropyl silane base-1H-pyrrolo-[2,3-in 500mL acetonitrile B] pyridin-3-yl)-methyl]-pyridine-2-base }-(4-methyoxy-benzyl)-t-butyl carbamate (136,21g, 32.4mmol add triethyl silicane (51.7mL, 324mmol) and trifluoroacetic acid (24.93mL, 324mmol) in).Reaction is 50 Stirred for several hour at DEG C, removes solvent under vacuo, and residue is absorbed in the dichloromethane of 250mL and adds The trifluoroacetic acid of 250mL.Mixture stirred for several hour under reflux, is then concentrated under vacuum.Residue is absorbed in acetic acid In ethyl ester and pour in aqueous potassium carbonate.Organic layer is separated, and is concentrated under vacuum and passes through silica gel column chromatography purification, described 0-5% methanol-eluted fractions in silica gel column chromatography dichloromethane.Suitably fraction combined and remove under vacuo solvent with Desired compound (137,5.2g, 20.29mmol, 62.7% yield) is provided.
Step 3-(5-{ [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base ammonia Base]-methyl }-pyrimidine-2-base) preparation of-methyl-amine (P-2095):
In the microwave phial of 2mL, the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base amine (137,9.72mg, 0.04mmol) and 2-methylamino-pyrimidine-5-formaldehyde (138,11.0mg, 0.08mmol) dissolve Ethanol in 600 μ L95: 5: in acetic acid, and add silicon dioxide carried cyanogen boron hydride (50mg, 1mmol/g, 0.05mmol).Reaction radiates 10 minutes in microwave at 160 DEG C.Phial is centrifuged with condensed silica and supernatant Liquid is moved in another phial by pipette.The silicon dioxide alcohol flushing of 500 μ L of residual, is centrifuged and is added by supernatant Enter to primary supernatant.The dimethyl that 400 μ L were removed and be dissolved in by the material obtained to solvent under vacuo is sub- Sulfone is with by HPLC purification.Sample is purified on Phenomenex C1 8 post (50mm × 10mm ID), and described post has water In the Mobile phase B of 0.1% trifluoroacetic acid in the mobile phase A of 0.1% trifluoroacetic acid, acetonitrile, at the stream of 6mL/min in 16 minutes The lower mobile 20-100%B of speed.The fraction being suitable for is collected and removes under vacuo solvent to provide desired compound.MS (ESI)[M+H+]+=378.3.
Be similar to the method for scheme 16 prepare the fluoro-3-{ of 5-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base amino]-methyl }-1-methyl isophthalic acid H-pyridin-2-ones P-2156
Wherein step 3 is replaced by the following step 3a:
The fluoro-3-{ of step 3a-5-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base amino]-methyl } preparation of-1-methyl isophthalic acid H-pyridin-2-ones (P-2156):
The fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base in 50mL acetonitrile Amine (137,3.99g, 15.59mmol) and 5-fluoro-1-methyl-2-oxo-1,2-dihydro-pyrido-3-formaldehyde (33,2.66g, 17.15mmol in), add triethyl silicane (9.96mL, 62.4mmol) and trifluoroacetic acid (4.80mL, 62.4mmol).Reaction Stirred for several hour at 80 DEG C, is then concentrated under vacuum and residue is absorbed in ethyl acetate and pours aqueous carbon into In acid potassium.Organic layer is separated, and is concentrated under vacuum, and residue is by silica gel column chromatography purification, described silica gel column chromatography By the 0-5% methanol-eluted fractions in dichloromethane.Suitably fraction is combined and is concentrated under vacuum, and residue methanol grinds Make to provide desired compound (P-2156,3.1g, 7.84mmol, 50.3% yield).
The method being similar to scheme 16, wherein step 3 is replaced by following step 3b:
Preparation N-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-C-benzene Base-Methanesulfomide P-2181
Step 3b-N-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-C- The preparation of phenyl-methane-sulfonamide (P-2181):
In phial, the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine The dichloromethane of (137,157mg, 0.614mmol) and 4mL and pyridine (149 μ L, 1.84mmol) mixed be incorporated in ice-water bath cold But to 0 DEG C.Add PHENYL-METHYL sulfonic acid chloride (139,0.234g, 1.23mmol) and react stirring 1 hour at 0 DEG C, then Warm to room temperature and be stirred overnight.Add aqueous saturated sodium bicarbonate and be extracted with ethyl acetate.Organic layer water and salt Water washs, and is dried the most over magnesium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column chromatography It is purified, the 0-10% methanol-eluted fractions in described silica gel column chromatography dichloromethane.Suitably fraction is combined and under vacuo Concentrate with the expectation compound (P-2181,39mg) being provided as yellow solid.MS(ESI)[M+H+]+=411.1.
Other compound is prepared according to the method (step 3 can be replaced with step 3a) of scheme 16, its conditional alterable, Such as, as those skilled in the art are readily available, optional solvent, reactant, response time, temperature can be used, excite bar Parts etc. change any one in solvent, reactant, response time, temperature, shooting condition or other response parameter.In step 1 3-iodo-5-methyl isophthalic acid-triisopropyl silicon is optionally replaced with applicable 1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine Alkyl-1H-pyrrolo-[2,3-b] pyridine 9；In step 1 with (5-formoxyl-pyrimidine-2-base)-(4-methyoxy-benzyl)-ammonia Base t-butyl formate optionally replaces (6-fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl)-t-butyl carbamate 83；And optionally replace 2-methylamino-pyrimidine-5-formaldehyde 138 with the aldehyde being suitable in step 3, prepare compound.Use this mistake Journey prepares following compounds.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
(5-fluoro-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-amine (P-1569), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoro Methvl-pyridinium-3-ylmethyl)-amine (P-1570), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1611), (6-chloro-pyridin-3-yl methyl)-[(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1612), [5-(5-chloro-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1613), [(5-is chloro-for 5- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 1614), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-1646), (5-fluoro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-Trifluoromethyl-1 H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1647), (6-chloro-pyridin-3-yl methyl)-[6-is fluoro- 5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1648), (5-fluoro-2-first Epoxide-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-amine (P-1649), [the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1650), [the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1651), [6-fluoro-5-(5-tri- Methyl fluoride-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)- Amine (P-1652), [the fluoro-5-of 6-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2- Methoxv-pyridine-3-ylmethyl)-amine (P-1653), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2049), (5-fluoro-2-methoxv-pyridine- 3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2061), [5- (5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(5-fluoro-2-methoxv-pyridine-3-Ji Jia Base)-amine (P-2064), (2,5-Dimethoxy-benzyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-2086), (3,5-Dimethoxy-benzyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2087), (6-chloro-pyridin-3-yl methyl)-[6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2088), (3-bromo-pyridin-4-yl methyl)- [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2089), [the fluoro-5-of 6- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-morpholine-4-base-pyridin-3-yl first Base)-amine (P-2090), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6- Morpholine-4-base-pyridin-3-yl methyl)-amine (P-2091), (3-chloro-pyridin-4-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2092), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridine-2-ylmethyl)-amine (P-2093), [6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(3-fluoro-pyridin-4-yl methyl)-amine (P- 2094), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-[2-(2,2,2-tri- Fluoro-ethyoxyl)-pyridin-3-yl methyl]-amine (P-2096), (2,6-dimethoxy-pyridin-3-ylmethyl)-[6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2097), (5-fluoro-2-mesyl-benzyl Base)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2098), (5- Chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-2099), (5-bromo-pyridine-2-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-2100), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(3-methvl-pyridinium-4-ylmethyl)-amine (P-2101), (the fluoro-benzyl of the chloro-5-of 3-)-[the fluoro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2102), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-fluoro-pyridin-3-yl methyl)-amine (P-2103), (3,5-diformazans Base-benzyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2104), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amine (P-2105), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(2-methyl-pvrimidine-5-ylmethyl)-amine (P-2106), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-(2-methylamino-pyridin-3-yl methyl)-amine (P-2107), (3,5-double-trifluoromethyl-benzyls Base)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2108), [6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-methoxv-pyridine-3-Ji Jia Base)-amine (P-2109), (2-ethyoxyl-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-2110), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-isopropoxy-pyridin-3-yl methyl)-amine (P-2111), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-methvl-pyridinium-2-ylmethyl)-amine (P-2112), (2-ring penta Epoxide-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2113), (2-cyclohexyloxy-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-amine (P-2114), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(2-trifluoromethylpyridin-3-ylmethyl)-amine (P-2115), (the chloro-5-of 2-fluoro-pyridin-4-yl first Base)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2116), 4- { [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-pyridine-2- Nitrile (P-2117), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(fluoro-pyrrole of 2- Pyridine-4-ylmethyl)-amine (P-2118), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(2-trifluoromethylpyridin-4-ylmethyl)-amine (P-2119), (2-chloro-pyridin-4-yl methyl)-[6-fluoro-5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2120), [the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-morpholine-4-base-pyridin-4-yl methyl)-amine (P- 2121), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-pyrrolidine-1- Base-pyridin-4-yl methyl)-amine (P-2122), (the chloro-2-of 5-fluoro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2123), (4-chloro-2-Methanesulfonyl-benzYl)-[6-is fluoro- 5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2124), (2-dimethylamino-benzyl Base)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2125), (2- Ethyl-pyrimidin-5-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2126), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2- Propyl-pyrimidin-5-ylmethyl)-amine (P-2127), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-isopropyl-pyrimidine-5-ylmethyl)-amine (P-2128), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-[2-(2-methox-etlayl)-pyrimidine-5-ylmethyl]-amine (P- 2129), (2-butyl-pyrimidine-5-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-2130), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(5-methvl-pyridinium-2-ylmethyl)-amine (P-2131), (3-fluoro-5-Methyl-benzvl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2132), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(3-methoxyl group-5-romethyl-benzy)-amine (P-2133), (3-is fluoro- 5-methyoxy-benzyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2134), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(3,4,5-tri- Methyoxy-benzyl)-amine (P-2150), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(5-pyrrolidin-1-yl-pyridine-2-ylmethyl)-amine (P-2151), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxyl group-6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2166), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-dimethylamino-6-trifluoro Methvl-pyridinium-3-ylmethyl)-amine (P-2167), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(6-methoxyl group-4-trifluoromethylpyridin-3-ylmethyl)-amine (P-2186), ethyl sulfonic acid (2-{ [6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-phenyl)-amide (P-2198), ethyl sulfonic acid (the fluoro-3-{ of 4-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-base amino]-methyl }-phenyl)-amide (P-2199) and ethyl sulfonic acid (the fluoro-5-{ of 3-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base amino]-methyl }-phenyl)-amide (P-2202).
Following table shows 1H-pyrrolo-[2, the 3-b] pyridine (the 2nd row) in step 1 and the aldehyde the (the 3rd of Boc-protection Row), and the aldehyde compound (the 4th row) in step 3 (or 3a, if shown in the 1st row) is to provide desired chemical combination Thing (the 5th row).During compound number provides in arranging the 1st, and the quality observed arranges the 6th.
Embodiment 17:[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5- Fluoro-pyridin-3-yl methyl) synthesis of-amine P-2001.
As shown in scheme 17, [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2- Base]-(5-fluoro-pyridin-3-yl methyl)-amine P-2001 is to make in five steps from 5-chloro-1H-pyrrolo-[2,3)] pyridine 1 Standby.
Scheme 17
The preparation of step-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-dimethyl-amines (140):
5-chloro-1H-pyrrolo-[2,3-b] pyridine (1,8.00g, 0.0524mol) in 250mL isopropanol adds salt Acid dimethylamine (4.79g, 0.0587mol) and formaldehyde (1.77g, 0.0589mol).Reaction is stirred at room temperature overnight, and returns subsequently Flow 4 hours.Reactant is concentrated, and is poured into water, and is extracted with ethyl acetate.Organic layer is dried and mistake on anhydrous sodium sulfate Filter.Filtrate is concentrated to provide crude compound (140,10.0g, 91%), and it is directly used in following step.
The preparation of step 2:5-chloro-3-dimethylamino methyl-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (141):
(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-two in 60.0mL DMF Methyl-amine (140,5.00g, 23.8mmol) adds sodium hydride (1.05g, in mineral oil 60%, 26.2mmol).10 minutes After, add Bis(tert-butoxycarbonyl)oxide (25,6.24g, 28.6mmol) and reaction is stirred at room temperature overnight, be subsequently poured in water And be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained It is purified by silica gel column chromatography, 5% methanol-eluted fractions in described silica gel column chromatography dichloromethane.Suitably fraction is combined And it is concentrated under vacuum to be provided as the expectation compound (141,5.20g) of white solid.
The preparation of step 3:5-chloro-3-chloromethyl-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (142):
In nitrogen, the 5-chloro-3-dimethylamino methyl in 100mL toluene-pyrrolo-[2,3-b] pyridine-1-carboxylic acid The tert-butyl ester (141,4.20g, 13.6mmol) adds ethyl chloroformate (1.48mL, 15.5mmol).Reaction is stirred at room temperature 2 Hour, then it is concentrated under vacuum and is combined with water and is extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters And filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, in described silica gel column chromatography hexane 25% ethyl acetate eluting with provide desired compound (142,1.60g).[tertbutyloxycarbonyl-(5-is fluoro-for step 4-3-{6- Pyridin-3-yl methyl)-amino]-2-fluoro-pyridin-3-yl methyl }-5-chloro-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (144) preparation:
(the bromo-6-of 5-fluoro-pyridine-2-base)-(fluoro-pyrrole of 5-in nitrogen at-25 DEG C, in 10.0mL oxolane Pyridine-3-ylmethyl) and-t-butyl carbamate (143,0.600g, 1.50mmol) middle addition isopropylmagnesium chloride (0.730mL, four 2.0M, 1.46mmol in hydrogen furan) and make reaction reach 5 DEG C in 1 hour.Then reaction is cooled to-35 DEG C, and adds CuCN 2LiCl (2.0mL, 0.75M, 1.5mmol in oxolane).After 5 minutes, add the 5-in 4.0mL oxolane chloro- 3-chloromethyl-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (142,0.300g, 0.996mmol) and make reaction little 1 Time interior reach room temperature.Reactant is introduced in liquor ammoniae dilutus and is extracted with ethyl acetate.Organic layer is separated, over sodium sulfate It is dried, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described silica gel column chromatography With the 20-100% ethyl acetate eluting in hexane.Suitably fraction is combined and solvent is removed to provide the phase under vacuo The compound (144,130mg) hoped.MS(ESI)[M+H+]+=586.2.
[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-is fluoro-for step 5- Pyridin-3-yl methyl) preparation of-amine (P-2001):
3-{6-[tertbutyloxycarbonyl-(5-fluoro-pyridin-3-yl methyl)-amino]-2-in 10.0mL dichloromethane is fluoro- Pyridin-3-yl methyl }-5-chloro-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (144,0.280g, 0.478mmol) adds Enter trifluoroacetic acid (1.00mL, 13.0mmol), and reaction is stirred at room temperature overnight.By itself and the similar independent reaction run Converge, and be concentrated under vacuum.The material obtained is combined with aqueous potassium carbonate and ethyl acetate and mixes.Water layer is separated And organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column layer Analysis is purified, 20% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and solvent exists It is removed under vacuum to provide desired compound (P-2001,99mg).MS(ESI)[M+H+]+=386.0.
3-[[the fluoro-6-of 2-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methylamino]-3-pyridine radicals] methyl]-1H-pyrrolo- The preparation of [2,3-b] pyridine-5-nitrile (P-2204)
To 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] the fluoro-N-of-6-[(5-fluoro-6-methoxyl group-3- Pyridine radicals) methyl] the middle N,N-dimethylacetamide adding 2mL of pyridine-2-amine (125mg, 0.27mmol).Mixture suspension By blasting argon-degassed.In argon at room temperature, in this suspension add zinc (5mg, 0.08mmol), 1,1 '-bis-(two Phosphenyl) ferrocene (6mg, 0.01mmol), zinc cyanide (0.01ml, 0.19mmol) and three (dibenzalacetone) two palladium (0) (7mg, 0.01mmol).Mixture is heated to 120 DEG C and keeps 2 hours and be cooled to room temperature.Reactant mixture ethyl acetate With water (+saturated sodium chloride) extraction.Organic layer water and saline washing, pass through MgSO4It is dried.Volatile matter is gone under vacuo Remove.Residue is suspended in acetonitrile and by sonicated 45 minutes.Precipitate is collected by filtration and washs with acetonitrile.Obtain brown Color solid (98mg, 88.8% yield).LC-MS shows a main peak with 98.6% purity.The structure of product passes through H1- NMR (DMSO-d6) determines.MS(ESI)[M+H]+=406.9.
Preparing other compound according to the method for scheme 17, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.-1H-pyrrolo-is replaced in step 1 with the 5-being suitable for [2,3-b] pyridine optionally replaces 5-chloro-1H-pyrrolo-[2,3-b] pyridine 1 and in step 4 with the bromine of the N-protected being suitable for Generation (or other be suitable for halo) compound optionally replace (the bromo-6-of 5-fluoro-pyridine-2-base)-(5-fluoro-pyridin-3-yl methyl)- T-butyl carbamate 143, prepares compound.This process is used to prepare following compounds.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
The fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrroles And [2,3-b] pyridine-5-nitrile (P-1654), 3-{6-[(6-chloro-pyridin-3-yl methyl)-amino]-2-fluoro-pyridin-3-yl first Base }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1655), the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-Ji Jia Base)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1656), 3-{2-fluoro-6-[(4-trifluoro Methvl-pyridinium-3-ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1657), 3- { the fluoro-6-of 2-[(6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine- 5-nitrile (P-1658), the fluoro-6-of 3-{2-[(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrole Cough up also [2,3-b] pyridine-5-nitrile (P-1659), the fluoro-6-of 3-{2-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridine- 3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-1660), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-2027), [the fluoro-5-of 6-(5-methoxyl group- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-2028), [6- Fluoro-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-Ji Jia Base)-amine (P-2029), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (6-methoxv-pyridine-3-ylmethyl)-amine (P-2030), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2031), (4-is chloro- Benzyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2032), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-2041), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(the fluoro-pyridine of 5-- 3-ylmethyl)-amine (P-2176), [(5-is fluoro-for the fluoro-N-of-6-for 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] 6-methoxyl group-3-pyridine radicals) methyl] pyridine-2-amine (P-2203), 3-[[the fluoro-6-of 2-[(5-fluoro-6-methoxyl group-3-pyridine radicals) Methylamino]-3-pyridine radicals] methyl]-1H-pyrrolo-[2,3-b] pyridine-5-nitrile (P-2204), the chloro-N-of 6-[(5-fluoro-2-methoxy Base-3-pyridine radicals) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl) methyl] pyridine-2-amine (P-2205) N-fluoro-with 6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5-[[5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-base] methyl] pyridine-2-amine (P-2206).
Following table shows 1H-pyrrolo-[2, the 3-b] pyridine compounds (the 2nd row) in step 1 and in step 4 The compound (the 3rd row) of halogen substiuted to provide desired compound (the 4th row).Compound number provides in arranging the 1st, and And during the quality of observation arranges the 5th.
The chloro-benzyl of embodiment 18:(3-)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1-methyl- 1H-pyrazole-3-yl] synthesis of-amine P-2006.
As shown in scheme 18, (the chloro-benzyl of 3-)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1- Methyl isophthalic acid H-pyrazole-3-yl]-amine P-2006 is from 5-(the chloro-benzylamino of 3-)-2-methyl-2H-pyrazoles-3-formaldehyde 145 and 5- Fluoro-3-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 146 is prepared in two steps.
Scheme 18
Step 1-[5-(the chloro-benzylamino of 3-)-2-methyl-2H-pyrazole-3-yl]-(5-fluoro-1-tri isopropyl silane base- 1H-pyrrolo-[2,3-b] pyridin-3-yl) preparation of-methanol (147):
In round-bottomed flask, the fluoro-3-of 5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (146, 0.33g, 0.79mmol) and 1.5mL oxolane combine and be cooled to-20 DEG C.Be added dropwise over isopropylmagnesium chloride (400 μ L, four 2.0M, 0.8mmol in hydrogen furan) and stir reaction and reach-5 DEG C.Reaction is cooled to-20 DEG C and adds in oxolane 5-(the chloro-benzylamino of 3-)-2-methyl-2H-pyrazoles-3-formaldehyde (145,0.090g, 0.36mmol) and stir reaction and reach To 0 DEG C.Reaction is concentrated under vacuum, and washs with diluted ethyl acetate and with saturated aqueous carbonic acid hydrogen sodium, then saline.Organic Layer is separated and is dried over sodium sulfate, filters and filtrate is by silica gel flash column chromatography, described silica gel flash column The gradient elution of 5-80% ethyl acetate in analysis hexane.Suitably fraction is combined and is concentrated under vacuum to provide desired Compound.MS(ESI)[M+H+]+=542.7,543.95.
Step 2-(the chloro-benzyl of 3-)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1-methyl isophthalic acid H- Pyrazole-3-yl] preparation of-amine (P-2006):
In 4mL dichloromethane [5-(the chloro-benzylamino of 3-)-2-methyl-2H-pyrazole-3-yl]-(5-fluoro-1-tri-is different Propyl silane base-1H-pyrrolo-[2,3-b] pyridin-3-yl)-methanol (147,0.070g, 0.13mmol) middle addition triethyl group silicon Alkane (0.210mL, 1.31mmol) and trifluoroacetic acid (0.100mL, 1.30mmol) and reaction are stirred at room temperature overnight.Reaction It is concentrated under vacuum, is subsequently adding ethyl acetate, then with the washing of potassium carbonate aqueous for 1M, then saline.Organic layer is at sulphuric acid It is dried on sodium, filters and filtrate is by silica gel flash column chromatography, in described silica gel rapid column chromatography dichloromethane 2-20% methanol elution gradient.Suitably fraction is combined and is concentrated under vacuum, and in the solid hexane obtained Ethyl acetate is washed to provide desired compound.
Preparing following compounds according to the method for scheme 18, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.Following compounds is passed through1H and13C NMR spectra and matter Stave is levied.
The chloro-N-of 6-[(5-fluoro-2-methoxyl group-3-pyridine radicals) methyl]-5-[(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-base) methyl] pyridine-2-amine (P-2205) and the fluoro-N-of 6-[(5-fluoro-6-methoxyl group-3-pyridine radicals) methyl]-5- [[5-(trifluoromethyl)-1H-pyrrolo-[2,3-b] pyridin-3-yl] methyl] pyridine-2-amine (P-2206).
Embodiment 19:[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1H-pyrazole-3-yl]-(4-is fluoro- Benzyl) synthesis of-amine P-2016.
As shown in scheme 19, [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1H-pyrazole-3-yl]- (the fluoro-benzyl of 4-)-amine P-2016 is from 5-(the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-formaldehyde 113 3-chloro-with 5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 4 is prepared in three steps.
Scheme 19
Step 1-(5-chloro-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridin-3-yl)-[5-(the fluoro-benzyl of 4- Amino)-2-(4-methyoxy-benzyl)-2H-pyrazole-3-yl] preparation of-methanol (148):
In round-bottomed flask, the chloro-3-of 5-iodo-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (4,1.7g, 3.9mmol) be combined with 1.3mL oxolane and be cooled to-20 DEG C.It is added dropwise over isopropylmagnesium chloride (2.0mL, oxolane Middle 2M, 4.0mmol) and react stirring at-5 DEG C.Reaction is cooled to-20 DEG C and adds the 5-in 2mL oxolane (the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazoles-3-formaldehyde (113,0.622g, 1.83mmol) and reacting Stir at 0 DEG C.Reaction is concentrated under vacuum, and washs with diluted ethyl acetate and with sodium bicarbonate and saline.Organic layer sulfur Acid sodium is dried and passes through silica gel column chromatography purification, with the 5-80% ethyl acetate eluting in hexane.Suitably fraction is combined also It is concentrated under vacuum to provide desired compound.MS(ESI)[M+H+]+=648.38 and 649.74.
Step 2-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1-(4-methyoxy-benzyl)-1H-pyrrole Azoles-3-base] preparation of-(the fluoro-benzyl of 4-)-amine (149):
In quartz phial, (5-chloro-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridin-3-yl)-[5- (the fluoro-benzylamino of 4-)-2-(4-methyoxy-benzyl)-2H-pyrazole-3-yl]-methanol (148,0.328g, 0.506mmol) with 20mL dichloromethane combine, add triethyl silicane (0.4mL, 2.0mmol), be subsequently added trifluoroacetic acid (0.2mL, 2.0mmol).Reaction is stirred at room temperature overnight, and is then concentrated under vacuum and adds ethyl acetate.This reactant 1M contains The potassium carbonate of water and saline washing, be dried with sodium sulfate, and by silica gel column chromatography purification, described silica gel column chromatography dichloromethane 2-20% methanol-eluted fractions in alkane.Suitably fraction is combined and is concentrated under vacuum, and ethyl acetate used further by solid Wash with hexane to provide desired compound.1H NMR is consistent with compound structure.
Step 3-[5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1H-pyrazole-3-yl]-(the fluoro-benzyl of 4- Base) preparation of-amine (P-2016):
In round-bottomed flask, [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-1-(4-methoxyl group-benzyl Base)-1H-pyrazole-3-yl]-(the fluoro-benzyl of 4-)-amine (149,0.060g, 0.13mmol) is dissolved in the trifluoroacetic acid of 5mL (60mmol) in, and react at 70 DEG C heated overnight.Reaction is cooled to room temperature, is then concentrated under vacuum and heats second Acetoacetic ester.Potassium carbonate and saline that this reactant 1M is aqueous wash, and are dried with sodium sulfate and pass through silica gel column chromatography and purify, institute State the 2-20% methanol-eluted fractions in silica gel column chromatography dichloromethane.Suitably fraction is combined and is concentrated under vacuum, and Solid with ethyl acetate and hexane wash to provide desired compound further.1H NMR is consistent with compound structure.MS (ESI)[M+H+]+=356.85.
The fluoro-N-of embodiment 20:5-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl] synthesis of-2-methoxy-nicotinamide P-2168.
As shown in scheme 20, the fluoro-N-of 5-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-2-methoxy-nicotinamide P-2168 is to make three steps from 5-fluoro-2-methoxv-pyridine-3-formaldehyde 37 Standby.
Scheme 20
The preparation of step 1-5-fluoro-2-methoxy-nicotinic acid (150):
In round-bottomed flask, 5-fluoro-2-methoxv-pyridine-3-formaldehyde (37,0.500g, 3.22mmol) and sodium chlorite (0.6734g, 5.957mmol), the Isosorbide-5-Nitrae-two of 30mLAlkane, the water of 10mL and sulfamic acid (2.39g, 24.6mmol) combine. Reactant mixture is stirred at room temperature 5 minutes, is subsequently poured in the water of 100mL and extracts by the ethyl acetate of 100mL.Organic Layer use water, saline washing, be dried the most over magnesium sulfate, filters and filtrate is concentrated under vacuum to provide desired compound (150,512mg), it need not be further purified in following step.
The preparation of step 2-5-fluoro-2-methoxyl group-nicotinoyl chlorine (nicotinoyl chloride) (151):
In round-bottomed flask, 5-fluoro-2-methoxy-nicotinic acid (150,250mg, 1.46mmol) and thionyl chloride (3.00mL, 41.1mmol) combine and suspension is stirred at room temperature 3 hours.Reaction is concentrated under vacuo and is dried to provide desired Compound, it need not be further purified in following step.
The fluoro-N-of step 3-5-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base] preparation of-2-methoxy-nicotinamide (P-2168):
In reaction flask, the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base Amine (137,100mg, 0.3902mmol) and 5-fluoro-2-methoxyl group-nicotinoyl chlorine (151,81.37mg, 0.4292mmol), 3.00mL Oxolane and pyridine (0.06312mL, 0.7804mmol) combine.Reaction is stirred at room temperature overnight, and is subsequently poured into aqueous 1N hydrochloric acid in and be extracted with ethyl acetate.Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum. The material obtained is purified by silica gel column chromatography, the 1-5% methanol-eluted fractions in described silica gel column chromatography dichloromethane.Close Suitable fraction is combined and is concentrated under vacuum to provide desired compound (P-2168,100mg).MS(ESI)[M+H+]+= 409.9。
Embodiment 21:[5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxy Base-pyridin-3-yl methyl) synthesis of-amine P-2017.
As shown in scheme 21, [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6- Methoxv-pyridine-3-ylmethyl)-amine P-2017 is from 5-bromo-1H-pyrrolo-[2,3-b] pyridine 152 and (5-formoxyl-pyrrole Pyridine-2-base)-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate 153 prepared in two steps.
Scheme 21
Step 1-{5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl)-methoxymethyl]-pyridine-2-base }- The preparation of (6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (154):
5-bromo-1H-pyrrolo-[2,3-b] pyridine in 50.0mL methanol under a nitrogen (152,0.622g, 3.16mmol add (5-Formyl-pyridin-2-base)-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate in) (153,1.05g, 3.06mmol) and potassium hydroxide (1.50g, 26.7mmol), and react be stirred at room temperature overnight.Reaction Thing is poured into water, and is extracted with ethyl acetate, and organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.Obtained The material obtained is purified by silica gel column chromatography, and the 20-100% ethyl acetate gradient in described silica gel column chromatography hexane is washed De-.Suitably fraction is combined and is concentrated under vacuum to provide desired compound (154,0.35g).{ 5-[(the bromo-1H-of 5- Pyrrolo-[2,3-b] pyridin-3-yl)-hydroxy-methyl]-pyridine-2-base }-(6-methoxv-pyridine-3-ylmethyl)-amino first Tert-butyl acrylate is formed the most in this step and can be separated, and is similar to the following step and carries out being reacted to form desired product Thing.Step 2-[5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3- Ylmethyl) preparation of-amine (P-2017):
{ 5-[(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl)-methoxymethyl]-pyrrole in 20.0mL acetonitrile Pyridine-2-base } the middle addition three of-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (154,0.35g, 0.63mmol) Ethylsilane (1.0mL, 6.3mmol) and trifluoroacetic acid (0.50mL, 6.5mmol), and react stirring 4 hours at 80 DEG C. Reaction is concentrated under vacuum and is combined with aqueous potassium carbonate and is extracted with ethyl acetate.Organic layer is filtered and filtrate exists Reduced under vacuum.The material obtained is purified by silica gel column chromatography, the 20-100% in described silica gel column chromatography hexane Ethyl acetate eluting.Suitably fraction combined and be concentrated under vacuum to provide desired compound (P-2017, 165.1mg)。MS(ESI)[M+H+]+=423.8,425.8.
It is similar to scheme 21, reacts in following single step 1a, prepare [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine P-1622.
Step 1a-[the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-first Epoxide-pyridin-3-yl methyl) preparation of-amine (P-1622):
In round-bottomed flask, 5-fluoro-1H-pyrrolo-[2,3-b] pyridine (155,0.115g, 0.845mmol) is with (6-is fluoro- 5-Formyl-pyridin-2-base)-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate (156,0.397g, 1.10mmol), the acetonitrile of 2.60mL, trifluoroacetic acid (0.325mL, 4.22mmol) and triethyl silicane (0.810mL, 5.07mmol) combine, and reaction is heated to reflux 3 hours.Reactant is poured into water and is extracted with ethyl acetate.Organic Layer saline washs, and is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column layer Analysis is purified, the ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and is concentrated under vacuum To provide desired compound (P-1622,28mg).MS(ESI)[M+H+]+=382.1.
Preparing other compound according to the method for scheme 21 (or single step 1a), its conditional alterable, such as, such as this Skilled person is readily available, and optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change molten Any one in agent, reactant, response time, temperature, shooting condition or other response parameter.In step 1, conjunction is optionally employed Suitable 1H-pyrrolo-[2,3-b] pyridine replaces 5-bromo-1H-pyrrolo-[2,3-b] pyridine 152 and optionally employs suitable aldehyde Replace (5-Formyl-pyridin-2-base)-(6-methoxv-pyridine-3-ylmethyl)-t-butyl carbamate 153, prepare chemical combination Thing.Further, any one or both in the methoxyl group formed in step 1 or hydroxy intermediate are the most anti- Should.This process is used to prepare following compounds.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
[the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-6-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amine (P-1506), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-1507), (6-chloro-pyridin-3-yl methyl)-[6-chloro-5-(1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1508), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1509), [the chloro-5-of 6-(1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1510), [the chloro-5-of 6- (1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P- 1511), [the chloro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-base Methyl)-amine (P-1512), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-amine (P-1528), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1529), (5-fluoro-pyridin-3-yl methyl)-[5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1530), (the chloro-pyridin-3-yl of 6- Methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1531), [5-(5- Methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)- Amine (P-1583), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1584), (5-fluoro-pyridin-3-yl methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1585), (6-chloro-pyridin-3-yl methyl)-[5-(5-methoxyl group- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1586), (5-fluoro-2-methoxv-pyridine-3-base Methyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1587), [5- (5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-1588), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1589), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1590), [the chloro-5-of 6-(5-methoxyl group-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1591), [6-is chloro- 5-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-chloro-pyridin-3-yl methyl)-amine (P-1592), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(the fluoro-2-of 5- Methoxv-pyridine-3-ylmethyl)-amine (P-1593), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1594), [the chloro-5-of 6-(5-methoxyl group-1H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1595), [the chloro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3- Ylmethyl)-amine (P-1596), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1623), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1624), (6-chloro-pyridin-3-yl methyl)-[6- Fluoro-5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1625), [6-fluoro-5-(5- Fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1626), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethyl- Pyridin-3-yl methyl)-amine (P-1627), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1628), [the fluoro-5-of 6-(5-fluoro-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1629), (5-fluoro-6-methoxyl group-pyrrole Pyridine-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 1638), (5-fluoro-pyridin-3-yl methyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-amine (P-1639), (6-chloro-pyridin-3-yl methyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-amine (P-1640), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-trifluoromethyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1641), (4-trifluoromethylpyridin-3-Ji Jia Base)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1642), (6-first Epoxide-pyridin-3-yl methyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-1643), (6-trifluoromethylpyridin-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1644), (2-methoxv-pyridine-3-ylmethyl)-[5-(5-Trifluoromethyl-1 H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1645), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1661), [5-(5-ring third Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1662), (6-chloro-pyridin-3-yl methyl)-[5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- Amine (P-1663), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-first Epoxide-pyridin-3-yl methyl)-amine (P-1664), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1665), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1666), [5-(5-cyclopropyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P- 1667), [5-(5-cyclopropyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine- 3-ylmethyl)-amine (P-1668), 3-{6-[(5-fluoro-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl-1H-pyrroles And [2,3-b] pyridine-4-nitrile (P-1719), 3-{6-[(6-chloro-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl- 1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1720), 3-{6-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]- Pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1721), 3-{6-[(4-trifluoromethylpyridin-3-base Methyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1722), 3-{6-[(6-methoxyl group- Pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P-1723), 3-{6- [(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-4-nitrile (P- 1724), 3-{6-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyrrole Pyridine-4-nitrile (P-1725), 3-{6-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H- Pyrrolo-[2,3-b] pyridine-4-nitrile (P-1726), [5-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2018), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2019), [5-(5-fluoro-1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2023), (the fluoro-benzyl of 2-)-[5-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2033) [5-(4-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-base Methyl)-amine (P-2170).
Following table shows in step 1 to provide 1H-pyrrolo-[2, the 3-b] pyridine of desired compound (the 4th row) Compound (the 2nd row) and aldehyde compound (the 3rd row).Compound number provides in arranging the 1st, and the quality observed is at the 5th row In.
According to the method for the following step 3, [5-(4-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine P-2170 reacts to provide (5-fluoro-2-methoxyl group-pyrrole further Pyridine-3-ylmethyl)-[5-(4-phenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine P-2171.
Step 3-5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(4-phenyl-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base] preparation of-amine (P-2171):
[5-(4-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amine (P-2170,1 equivalent), phenylboric acid (157,1.5 equivalent) and four (triphenyl phasphine) palladium (0) (catalyst) Combine with the aqueous carbonic acid potassium (1.00M, 3 equivalents) of 0.33mL and the acetonitrile of 0.34mL.The mixture obtained in microwave Heat at 120 DEG C 10 minutes, heat 55 minutes at 130 DEG C subsequently.Mixture ethyl acetate and water dilute and water layer quilt Separate and be extracted with ethyl acetate.Organic layer is combined and washs with saline, is dried over sodium sulfate, filters and filtrate exists Reduced under vacuum.Obtained material passes through silica gel column chromatography purification, described silica gel column chromatography methanol and dichloromethane eluent.Suitable The fraction closed is combined and is concentrated under vacuum to provide desired compound.
Embodiment 22:[5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-tri- Methyl fluoride-pyridin-3-yl methyl) synthesis of-amine P-1717.
As shown in scheme 22, [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine P-1717 is from 4-acetenyl-1-tri isopropyl silane base-1H-pyrroles And [2,3-b] pyridine 161 and (5-Formyl-pyridin-2-base)-two-t-butyl carbamate 162 prepared in three steps 's.
Scheme 22
Step 1-{5-[(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxy-methyl]-pyridine-2-base }- The preparation of two-t-butyl carbamate (163):
In round-bottomed flask, 4-acetenyl-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine (161, 0.321g, 1.08mmol) and (5-Formyl-pyridin-2-base)-two-t-butyl carbamate (162,0.416g, 1.29mmol), methanol and the potassium hydroxide (0.302g, 5.38mmol) of 2.1mL combines and is stirred at room temperature 24 hours.Instead Apply aqueous 0.1N hydrochloric acid to neutralize, be then extracted with ethyl acetate 3 times.In conjunction with organic layer with saline wash, then at sulfur It is dried on acid sodium, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described silica gel Column chromatography methanol and dichloromethane eluent.Suitably fraction is combined and is concentrated under vacuum to provide desired compound (163,229mg).MS(ESI)[M-H+]-=337.2.
The system of step 2-5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine (164) Standby:
In round-bottomed flask, { 5-[(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxy-methyl]-pyrrole Pyridine-2-base }-two-t-butyl carbamate (163,0.225g, 0.484mmol) and trifluoroacetic acid (0.70mL, 9.1mmol), three The acetonitrile of ethylsilane (1.8mL, 11.0mmol) and 5.2mL combines, and reaction is heated to reflux 6 hours.Reactant falls Enter in water and be extracted with ethyl acetate.Organic layer saline washs, and is dried the most over sodium sulfate, filters and filtrate is very Empty lower concentration.The material obtained is purified by silica gel column chromatography, described silica gel column chromatography methanol and dichloromethane eluent. Suitably fraction is combined and is concentrated under vacuum to provide desired compound (164,57mg).MS(ESI)[M+H+]+= 248.9。
Step 3-[5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoro Methvl-pyridinium-3-ylmethyl) preparation of-amine (P-1717):
In round-bottomed flask, 5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base amine (164,0.055g, 0.22mmol) and 6-trifluoromethylpyridin-3-formaldehyde (160,50.4mg, 0.288mmol), 0.682mL Acetonitrile, trifluoroacetic acid (0.0853mL, 1.11mmol) and triethyl silicane (0.212mL, 1.33mmol) combine, and react quilt Heat with backflow 3 hours.Reactant is poured into water and is extracted with ethyl acetate.Organic layer saline washs, then at sulphuric acid It is dried on sodium, filters and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, described silicagel column Chromatography methanol and dichloromethane eluent.Suitably fraction is combined and is concentrated under vacuum to provide desired compound (P- 1717,9.3mg).MS(ESI)[M+H+]+=408.5.
Prepare other compound according to the method for scheme 22, its conditional alterable, such as, such as those skilled in the art It is readily available, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, anti- Any one between Ying Shi, in temperature, shooting condition or other response parameter.In step 3,6-tri-is optionally replaced with suitable aldehyde Methyl fluoride-pyridine-3-formaldehyde 160, prepares compound.This process is used to prepare following compounds.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
[5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-6-methoxy Base-pyridin-3-yl methyl)-amine (P-1711), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1712), (6-chloro-pyridin-3-yl methyl)-[5-(4-acetenyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1713), [5-(4-acetenyl-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1714), [5- (4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-1715), [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxy Base-pyridin-3-yl methyl)-amine (P-1716) and [5-(4-acetenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1718).
Following table shows in step 3 to provide the aldehyde compound (the 2nd row) of desired compound (the 3rd row).Chemical combination During thing numbering provides in arranging the 1st, and the quality observed arranges the 4th.
Embodiment 23:(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-{ the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrrole Azoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base } synthesis of-amine P-1703.
As shown in scheme 23, (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-the fluoro-5-of 6-[5-(1-piperidin-4-yl- 1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-amine P-1703 is from 1-benzene sulfonyl The bromo-3-of base-5-iodo-1H-pyrrolo-[2,3-b] pyridine 165 and (6-fluoro-5-Formyl-pyridin-2-base)-(4-methoxyl group-benzyl Base)-t-butyl carbamate 83 prepared in five steps.
Scheme 23
Step 1-{5-[(1-benzenesulfonyl-5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxy-methyl]-6- Fluoro-pyridine-2-base }-the preparation of (4-methyoxy-benzyl)-t-butyl carbamate (166):
The bromo-3-of 1-benzenesulfonyl-5-iodo-1H-pyrrolo-[2,3-in 7mL oxolane at-50 DEG C in nitrogen B] pyridine (165,1.00g, 2.16mmol) solution is slowly added into isopropylmagnesium chloride (1.18mL, 2.35mmol).React Be warmed to 5 DEG C in 70 minutes, be subsequently cooled to-45 DEG C, and add in 3.0mL oxolane (6-fluoro-5-formoxyl- Pyridine-2-base)-(4-methyoxy-benzyl)-t-butyl carbamate (83,0.678g, 1.88mmol).To react at 2-3 hour Inside warm to room temperature.Reactant mixes with aqueous 1N citric acid and is extracted with ethyl acetate.Organic layer water and salt washing Wash, be dried the most over magnesium sulfate, filter and filtrate is concentrated under vacuum.The material obtained is pure by silica gel column chromatography Change, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction is combined and is concentrated under vacuum to be provided as The expectation compound (166,1.155g) of white solid.MS(ESI)[M+H+]+=696.4 and 698.3.
Step 2-5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2- The preparation of base amine (167):
In round-bottomed flask, { 5-[(1-benzenesulfonyl-5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl)-hydroxyl-first Base]-6-fluoro-pyridine-2-base }-(4-methyoxy-benzyl)-t-butyl carbamate (166,1.15g, 1.65mmol) and 50mL 1,2-dichloroethanes, trifluoroacetic acid (0.635mL, 8.24mmol) and triethyl silicane (1.32mL, 8.24mmol) combine.Instead Should heat under reflux 20 hours, then be concentrated under vacuum.Residue is dissolved in the trifluoroacetic acid of 10mL and in room temperature Lower stirring 18 hours, is then concentrated under vacuum and is combined with aqueous sodium bicarbonate and is extracted with ethyl acetate.Organic layer Wash with sodium bicarbonate, water and saline, be dried the most over magnesium sulfate, filter and filtrate is concentrated under vacuum.Obtained Material is purified by silica gel column chromatography, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction is combined And be concentrated under vacuum to provide desired compound (167,403mg).MS(ESI)[M-H+]-=460.8 and 462.8.
Step 3-[5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2- Base] preparation of-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (168):
5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-in 10mL acetonitrile is fluoro- Pyridine-2-base amine (167,0.342g, 0.741mmol) middle addition 5-fluoro-2-methoxv-pyridine-3-formaldehyde (37,0.118g, 0.763mmol), triethyl silicane (0.529mL, 3.71mmol) and trifluoroacetic acid (0.286mL, 3.71mmol).Reaction is 80 Heat 4 hours at DEG C, be then concentrated under vacuum and be combined with aqueous potassium carbonate and be extracted with ethyl acetate.Organic layer is used Water and saline washing, be dried the most over magnesium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel Column chromatography is purified, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction is combined and the denseest Contracting is with the expectation compound (168,367mg) being provided as pale solid.MS(ESI)[M-H+]-=599.6 and 601.6.
Step 4-4-[4-(the fluoro-6-of 1-benzenesulfonyl-3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-ammonia Base]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-pyrazol-1-yl]-piperidines-1-carboxylic acid tert-butyl ester (170) and 4-[4-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }- 1H-pyrrolo-[2,3-b] pyridine-5-base)-pyrazol-1-yl] preparation of-piperidines-1-carboxylic acid tert-butyl ester (P-1702):
In microwave phial, in conjunction with [5-(1-benzenesulfonyl-5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-6-fluoro-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (168,218mg, 0.363mmol) and 4- [4-(4,4,5,5-tetramethyls-[1,3,2] dioxaborolanes-2-base)-pyrazol-1-yl]-piperidines-1-carboxylic acid tert-butyl ester (169,205mg, 0.545mmol) also adds acetonitrile and the potassium carbonate (1.11mL, 1.0M in water, 1.11mmol) of 2.22mL.So After by [1,1 '-bis-(diphenyl phosphine) ferrocene]) dichloro palladium] and (II) (27mg, 0.037mmol) add in reactant mixture also And heat 5 minutes at 160 DEG C in microwave.Add water and mixture is extracted with ethyl acetate.Organic layer water and saline Washing, is dried the most over magnesium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column chromatography quilt Purification, described silica gel column chromatography ethyl acetate and Hex.Suitably fraction is combined and is concentrated under vacuum to provide Desired compound (170,137mg) and (P-1702,66mg).170MS(ESI)[M+H+]+=770.7.P-1702MS(ESI) [M+H+]+=631.1.
Step 5-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles- 4-yl)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base } preparation of-amine (P-1703):
In phial, 4-[4-(the fluoro-6-of 1-benzenesulfonyl-3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)- Amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-pyrazol-1-yl]-piperidines-1-carboxylic acid tert-butyl ester (170,0.137g, 0.178mmol) is dissolved in the 7.0mL methanol solution of potassium hydroxide (0.392g, 6.99mmol), and instead Should heat 3 hours at 50 DEG C.Adding aqueous 1M citric acid, then reactant is extracted with ethyl acetate.Organic layer water and Saline washs, and is dried the most over magnesium sulfate, filters and filtrate is concentrated under vacuum.[([(5-is fluoro-for the fluoro-6-of 3-{2-for 4-for 4- 2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-pyrazoles- 1-yl]-piperidines-1-carboxylic acid tert-butyl ester (P-1702,56mg, 0.0888mmol) is combined with this reactant and adds the two of 10mL Chloromethanes and trifluoroacetic acid (0.50mL, 6.5mmol), be then stirred at room temperature 2 hours.Aqueous saturated sodium bicarbonate is added Enter until pH～8, be then concentrated under vacuum and add ethyl acetate and water.Organic layer is separated and by aqueous saturated carbon Acid hydrogen sodium washing, is then dried with magnesium sulfate, filters and filtrate is concentrated under vacuum to be provided as the expectation of yellow solid Compound (P-1703,74mg).MS(ESI)[M+H+]+=631.1.
Preparing other compound according to the method for scheme 23, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.In step 3, optionally replace 5-fluoro-with suitable aldehyde 2-methoxv-pyridine-3-formaldehyde 37, prepares compound.This process is used to prepare following compounds.Compound in following table leads to Cross1H and13C NMR spectra and mass spectral characteristi.
(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-amine (P-1704), the fluoro-5-of 6-[5-(1-piperidin-4-yl- 1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-(5-fluoro-pyridin-3-yl methyl)- Amine (P-1705), (6-chloro-pyridin-3-yl methyl)-{ the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrroles And [2,3-b] pyridin-3-yl methyl]-pyridine-2-base-amine (P-1706), { the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrrole Azoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base)-(4-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-1707), { the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl]-pyridine-2-base-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1708), { the fluoro-5-of 6-[5-(1-piperidines-4- Base-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl]-pyridine-2-base }-(6-trifluoromethylpyridin- 3-ylmethyl)-amine (P-1709) and { the fluoro-5-of 6-[5-(1-piperidin-4-yl-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl]-pyridine-2-base }-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1710).
Following table shows in step 3 to provide the aldehyde compound (the 2nd row) of desired compound (the 3rd row).Chemical combination During thing numbering provides in arranging the 1st, and the quality observed arranges the 4th.
Embodiment 24:N-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl Methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base) synthesis of-acetamide P-1669.
As shown in scheme 24, N-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyrrole Pyridine-3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide P-1669 is from the 5-iodo-pyrrolo-of bromo-3-[2,3- B] pyridine-1-carboxylic acid tert-butyl ester 171 and (6-fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl)-carbamic acid uncle Butyl ester 83 is prepared in four steps.
Scheme 24
The bromo-3-of step 1-5-({ 6-[tertbutyloxycarbonyl-(4-methyoxy-benzyl)-amino] the fluoro-pyridin-3-yl of-2-}-hydroxyl Base-methyl) preparation of-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (172):
The bromo-3-of 5-iodo-pyrrolo-[2,3-b] pyridine-1-in the 500mL oxolane at-20 DEG C in nitrogen Carboxylic acid tert-butyl ester (171,1 equivalent) adds isopropylmagnesium chloride (1.2 equivalent).Reaction was warmed to 0 DEG C in 30 minutes, so After be cooled to-40 DEG C, be subsequently added (6-fluoro-5-Formyl-pyridin-2-base)-(4-methyoxy-benzyl) tertiary fourth of-carbamic acid Ester (83,0.8 equivalent).Reaction was warmed to 0 DEG C in 1 hour, then with saline cancellation and be extracted with ethyl acetate.Organic Layer is concentrated under vacuum to provide desired compound, and it need not be further purified in following step.
The preparation of step 2-5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base amine (173):
The bromo-3-of 5-({ 6-[tertbutyloxycarbonyl-(4-methyoxy-benzyl)-amino] the fluoro-pyrrole of-2-in 451mL acetonitrile Pyridine-3-base }-hydroxy-methyl)-pyrrolo-[2,3-b] pyridine-1-carboxylic acid tert-butyl ester (172,1 equivalent) middle addition triethyl silicane (10 equivalent) and trifluoroacetic acid (10 equivalent).Reaction stirred for several hour at 80 DEG C, is then concentrated under vacuum.The thing obtained Matter is absorbed in the dichloromethane of 250mL and adds the trifluoroacetic acid of 250mL, the most under reflux stirred for several hour.Instead The material that should be concentrated under vacuum and be obtained is absorbed in ethyl acetate and adds aqueous saturated potassium carbonate extraction.Have Machine layer is concentrated under vacuum and obtained material is by silica gel column chromatography purification, in described silica gel column chromatography dichloromethane 0-5% methanol-eluted fractions.The fraction being suitable for is combined and is concentrated under vacuum to provide desired compound.
[5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(5-is fluoro-for step 3- 2-methoxv-pyridine-3-ylmethyl) preparation of-amine (P-1497):
To 5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base amine (173,1 equivalent) In 2-methoxv-pyridine-3-formaldehyde (37,1 equivalent) fluoro-with 5-, (4 work as addition triethyl silicane (4 equivalent) and trifluoroacetic acid Amount).Reaction stirred for several hour at 80 DEG C, is then concentrated under vacuum.The material obtained is absorbed in ethyl acetate also Add aqueous potassium carbonate extraction.Organic layer is concentrated under vacuum, then with dichloromethane development to provide desired compound.
Step 4-N-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl first Base }-1H-pyrrolo-[2,3-b] pyridine-5-base) preparation of-acetamide (P-1669):
In sealable phial, [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) the fluoro-pyridine of-6-- 2-yl]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1497,1 equivalent) is dissolved in the two of 25mLIn alkane.Add Cesium carbonate (2.1 equivalent), Hydro-Giene (Water Science). (I) (1.5 equivalent), acetamide (174,22 equivalent) and N, N '-dimethyl ethylenediamine (17 Equivalent).Phial is sealed and heated overnight at 100 DEG C.Reaction is injected towards in ethyl acetate and saline and extracts.Organic The material that layer is concentrated under vacuum and is obtained is dissolved in dichloromethane and by silica gel column chromatography purification, described silicagel column 0-10% methanol-eluted fractions in chromatography dichloromethane.Suitably fraction is concentrated, and material be dissolved in oxolane with C18 reversed-phase column is further purified, described C18 reversed-phase column 0-100% methanol (there is 10% oxolane)/water elution. Suitably fraction is combined and is concentrated under vacuum.The material methyl tertiary butyl ether(MTBE) development that obtained also is filtered, and uses methyl-tert Butyl ether, then heptane wash.Solid is dried under vacuum to provide desired compound.
Preparing other compound according to the method for scheme 24, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.In step 3 with the suitable aldehyde fluoro-2-of optionally substituted 5- Methoxv-pyridine-3-formaldehyde 37, and in step 4 with the optionally substituted acetamide of Methanesulfomide 174, prepare compound.Use This process prepares following compounds.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
N-(the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H- Pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1670), N-(the fluoro-6-of 3-{2-[(5-fluoro-pyridin-3-yl methyl)-ammonia Base]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1671), ([(6-is chloro-for 3-{6-for N- Pyridin-3-yl methyl)-amino]-2-fluoro-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P- 1672), N-(the fluoro-6-of 3-{2-[(4-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo- [2,3-b] pyridine-5-base)-acetamide (P-1673), N-(the fluoro-6-of 3-{2-[(6-methoxv-pyridine-3-ylmethyl)-ammonia Base]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1674), N-(the fluoro-6-of 3-{2- [(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)- Acetamide (P-1675), N-(the fluoro-6-of 3-{2-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }- 1H-pyrrolo-[2,3-b] pyridine-5-base)-acetamide (P-1676), N-(the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine- 3-ylmethyl)-amino]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1677), N- (the fluoro-6-of 3-{2-[(5-fluoro-pyridin-3-yl methyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5- Base)-Methanesulfomide (P-1678), N-(3-{6-[(6-chloro-pyridin-3-yl methyl)-amino]-2-fluoro-pyridin-3-yl methyl }- 1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1679), N-(the fluoro-6-of 3-{2-[(5-fluoro-2-methoxyl group-pyrrole Pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P- 1680), N-(the fluoro-6-of 3-{2-[(4-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo- [2,3-b] pyridine-5-base)-Methanesulfomide (P-1681), N-(the fluoro-6-of 3-{2-[(6-methoxv-pyridine-3-ylmethyl)-ammonia Base]-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1682), N-(the fluoro-6-of 3-{2- [(6-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-base)- Methanesulfomide (P-1683) and N-(the fluoro-6-of 3-{2-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl first Base }-1H-pyrrolo-[2,3-b] pyridine-5-base)-Methanesulfomide (P-1684).
Following table shows the aldehyde compound (the 2nd row) in step 3 and the acetamide in step 4 or Methanesulfomide (the 3rd row) are to provide desired compound (the 4th row).Compound number provides in arranging the 1st, and the quality observed is the 5th In row.
[the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-is fluoro- 2-methoxv-pyridine-3-ylmethyl)-amine P-1688 be from [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- 6-fluoro-pyridine-2-base] prepared by-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine P-1497 4a through the following steps.
Step 4a-[the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- The preparation of (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1688):
In sealable phial, [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl) the fluoro-pyridine of-6-- 2-yl]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1497,1 equivalent) is dissolved in the dimethyl sulfoxide of 5mL. Add Hydro-Giene (Water Science). (I) (0.2 equivalent), L-PROLINE (0.2 equivalent), methane sulfinic acid sodium (175,1.2 equivalent) and hydroxide Sodium (0.2 equivalent).Phial is sealed and heated overnight at 100 DEG C, and (0.2 works as to be subsequently adding other Hydro-Giene (Water Science). (I) Amount), L-PROLINE (0.2 equivalent), methane sulfinic acid sodium (1.2 equivalent) and sodium hydroxide (0.2 equivalent), and react and sealed And at 120 DEG C heated overnight.Reaction is injected towards in ethyl acetate and saline and extracts.Organic layer be concentrated under vacuum and The material obtained is dissolved in oxolane with purification on C18 reversed-phase column, described C18 reversed-phase column 0-100% methanol (tool Have 10% oxolane)/water elution.The fraction being suitable for is combined and is concentrated under vacuum.The material methyl-tert fourth obtained Base ether development is also filtered, with methyl tertiary butyl ether(MTBE), then heptane wash.Solid is dried under vacuum to provide desired chemical combination Thing.
The fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrroles And [2,3-b] pyridine-5-acid methylamide P-1696 be from [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- 6-fluoro-pyridine-2-base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine P-1497 4b through the following steps and step 5 make Standby.
The fluoro-6-of step 4b-3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }- The preparation of 1H-pyrrolo-[2,3-b] pyridine-5-carboxylate methyl ester (P-1693):
In 2L Paar steel cylinder, [5-(5-bromo-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2- Base]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1497,1 equivalent), triethylamine (2 equivalent) and [1,1 '-bis-(two Phosphenyl) ferrocene]) dichloro palladium] (II) (0.03 equivalent) be combined with the methanol of 300ml.React the carbon monoxide at 100psi In at 100 DEG C heated overnight.Reactant mixture is concentrated under vacuum, and is absorbed in ethyl acetate and washes with water.Organic Layer is concentrated under vacuum, and residue is dissolved in dichloromethane and by silica gel column chromatography purification, described silica gel column chromatography is with two 0-10% methanol-eluted fractions in chloromethanes.Suitably fraction is combined and is concentrated under vacuum to provide desired compound.
The fluoro-6-of step 5-3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }- The preparation of 1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1696):
In sealable phial, the fluoro-6-of 3-{2-[(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amino]-pyrrole Pyridine-3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-carboxylate methyl ester (P-1693,1 equivalent) with methylamine (2N in methanol, 15 Equivalent) size mixing, seal and heated overnight at 50 DEG C.Add other methylamine (2N, 15 equivalents in methanol) and add at 50 DEG C Heat is overnight.Reaction is concentrated under vacuum, and residue is dissolved in oxolane with purification on C18 reversed-phase column, and described C18 is anti-phase Post 0-100% methanol (there is 10% oxolane)/water elution.Suitably fraction is combined and is concentrated under vacuum.Obtained Material ethyl acetate/heptane development and filter, use heptane wash.Solid is dried under vacuum to provide desired chemical combination Thing.
According to the method for scheme 24, using step 4a or step 4b and step 5, prepare other compound, its conditional can Change, such as, as those skilled in the art are readily available, can use optional solvent, reactant, response time, temperature, swash Clockwork spring parts etc. change any one in solvent, reactant, response time, temperature, shooting condition or other response parameter.In step With the optionally substituted 5-of the aldehyde fluoro-2-methoxv-pyridine-3-formaldehyde 37 being suitable in 3, prepare compound.Use under the preparation of this process Row compound.Compound in following table passes through1H and13C NMR spectra and mass spectral characteristi.
[the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(5-is fluoro- 6-methoxv-pyridine-3-ylmethyl)-amine (P-1685), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridine- 3-ylmethyl)-pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1686), (6-chloro-pyridin-3-yl methyl)-[6- Fluoro-5-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1687), [6-is fluoro- 5-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-base Methyl)-amine (P-1689), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1690), [the fluoro-5-of 6-(5-mesyl-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1691), [6-fluoro-5-(5-first Sulfonyl-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-1692), the fluoro-6-of 3-{2-[(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrole Cough up also [2,3-b] pyridine-5-acid methylamide (P-1694), the fluoro-6-of 3-{2-[(5-fluoro-pyridin-3-yl methyl)-amino]-pyrrole Pyridine-3-ylmethyl }-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1695), 3-{6-[(the chloro-pyridin-3-yl of 6- Methyl)-amino]-2-fluoro-pyridin-3-yl methyl-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1697), 3- { the fluoro-6-of 2-[(4-trifluoromethylpyridin-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyrrole Pyridine-5-acid methylamide (P-1698), the fluoro-6-of 3-{2-[(6-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl first Base }-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1699), the fluoro-6-of 3-{2-[(6-trifluoromethylpyridin-3- Ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-acid methylamide (P-1700) and 3-{2- Fluoro-6-[(2-methoxv-pyridine-3-ylmethyl)-amino]-pyridin-3-yl methyl }-1H-pyrrolo-[2,3-b] pyridine-5-carboxylic Acid Methanamide (P-1701).
Following table shows the aldehyde compound (the 2nd row) in step 3 and step 4a used in step 4 or step 4b/5 (the 3rd row) is to provide desired compound (the 4th row).Compound number provides in arranging the 1st, and the quality observed exists In 5th row.
The chloro-benzyl of embodiment 25:(2-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base] synthesis of-amine P-2034.
As shown in scheme 25, (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine P-2034 is from (the chloro-benzyl of 2-)-(6-fluoro-5-Formyl-pyridin-2-base)-carbamic acid The tert-butyl ester 48 and 3-iodo-5-methoxyl group-1-tri isopropyl silane base-1H-pyrrolo-[2,3-b] pyridine 5 is made in two steps Standby.
Scheme 25
Step 1-(the chloro-benzyl of 2-)-{ the fluoro-5-of 6-[hydroxyl-(5-methoxyl group-1-tri isopropyl silane base-1H-pyrrolo- [2,3-b] pyridin-3-yl)-methyl]-pyridine-2-base } preparation of-t-butyl carbamate (176):
3-iodo-5-methoxyl group-1-tri isopropyl silane base in the 6.8mL oxolane at-50 DEG C in nitrogen- 1H-pyrrolo-[2,3-b] pyridine (5,0.49g, 1.14mmol) is slowly added into isopropylmagnesium chloride (0.569mL, oxolane Middle 2.0M, 1.14mmol).Reaction was warmed to 5 DEG C in 70 minutes, is subsequently cooled to-60 DEG C and adds 30.0mL tetrahydrochysene (the chloro-benzyl of 2-) in furan-(6-fluoro-5-Formyl-pyridin-2-base)-t-butyl carbamate (48,0.23g, 0.63mmol).Reaction was warmed to room temperature in 1 hour, is subsequently poured in aqueous ammonium chloride and is extracted with ethyl acetate. Organic layer is dried over sodium sulfate, filters and filtrate is concentrated under vacuum.The material obtained passes through silica gel column chromatography quilt Purification, the 20-100% ethyl acetate eluting in described silica gel column chromatography hexane.Suitably fraction is combined and in vacuum Lower removal solvent is to be provided as the expectation compound (176,0.400g) of white solid.MS(ESI)[M+H+]+=669.4.
Step 2-(the chloro-benzyl of 2-)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrrole Pyridine-2-base] preparation of-amine (P-2034):
(the chloro-benzyl of 2-) in 20.0mL dichloromethane-{ the fluoro-5-of 6-[hydroxyl-(5-methoxyl group-1-triisopropyl silicon Alkyl-1H-pyrrolo-[2,3-b] pyridin-3-yl)-methyl]-pyridine-2-base }-t-butyl carbamate (176,400mg, Triethyl silicane (2.00mL, 12.5mmol) and trifluoroacetic acid (1.00mL, 13.0mmol) is added in 0.598mmol).React Stir 4 hours under room temperature, be subsequently poured in aqueous potassium carbonate and be extracted with ethyl acetate.Organic layer is done over sodium sulfate Dry, filter and filtrate is concentrated under vacuum.The material obtained is purified by silica gel column chromatography, and described silica gel column chromatography is used 20-100% ethyl acetate eluting in hexane.Suitably fraction is combined and removes solvent under vacuo to be provided as white admittedly The expectation compound (P-2034,60.7mg) of body.MS(ESI)[M+H+]+=397.1.
Preparing other compound according to the method for scheme 25, its conditional alterable, such as, as those skilled in the art hold Easily obtain, optional solvent, reactant, response time, temperature, shooting condition etc. can be used to change solvent, reactant, reaction Any one in time, temperature, shooting condition or other response parameter.Use suitable 3-iodo-1-triisopropyl in step 1 Silylation-1H-pyrrolo-[2,3-b] pyridine replaces 3-iodo-5-methoxyl group-1-tri isopropyl silane base-1H-pyrrolo-[2,3- B] pyridine 5 and use suitable aldehyde replace (the chloro-benzyl of 2-)-(6-fluoro-5-Formyl-pyridin-2-base) the tertiary fourth of-carbamic acid Ester 48, prepares compound.This process is used to prepare following compounds.Compound in following table passes through1H and13C NMR spectra and Mass spectral characteristi.
(6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-1499), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1500), [the fluoro-5-of 6-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1501), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5- (1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1513), (5-fluoro-pyridin-3-yl methyl)- [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1514), (6-chloro-pyridin-3-yl first Base)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1515), [5-(1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1516), (6-methoxy Base-pyridin-3-yl methyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1517), [5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1518), (2-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2- Base]-amine (P-1519), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyrimidine-2-base]-amine (P-1520), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]- (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-1521), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-thiazol-2-yl]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1522), (6-chloro-pyridin-3-yl methyl)-[chloro-5-of 4- (1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1523), [4-chloro-5-(1H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-thiazol-2-yl]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-1524), [the chloro-5-of 4- (1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 1525), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-methoxv-pyridine-3-base Methyl)-amine (P-1526), [the chloro-5-of 4-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(2-methoxy Base-pyridin-3-yl methyl)-amine (P-1527), (6-methoxv-pyridine-3-ylmethyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1532), (5-fluoro-6-methoxv-pyridine-3-Ji Jia Base)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1533), (5-fluoro-pyridin-3-yl methyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-amine (P-1534), (6-chloro-pyridin-3-yl methyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-1535), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[6-methyl-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1536), [6-methyl-5-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1537), [6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-trifluoromethylpyridin- 3-ylmethyl)-amine (P-1538), (2-methoxv-pyridine-3-ylmethyl)-[6-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1539), (6-methoxv-pyridine-3-ylmethyl)-[3-methyl-5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1554), (5-fluoro-6-methoxyl group- Pyridin-3-yl methyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1555), (5-fluoro-pyridin-3-yl methyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-amine (P-1556), (6-chloro-pyridin-3-yl methyl)-[3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1557), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[3-first Base-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1558), [3-methyl-5- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)- Amine (P-1559), [3-methyl-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-tri- Methyl fluoride-pyridin-3-yl methyl)-amine (P-1560), (2-methoxv-pyridine-3-ylmethyl)-[3-methyl-5-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1561), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1562), (5-is fluoro- 6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-amine (P-1563), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]- (5-fluoro-pyridin-3-yl methyl)-amine (P-1564), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1565), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)- [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-1566), [the fluoro-5-of 3- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)- Amine (P-1567), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxy Base-pyridin-3-yl methyl)-amine (P-1568), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1579), (5-fluoro-pyridin-3-yl methyl)-[5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1580), (6-chloro-pyridin-3-yl methyl)- [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-1581), [5-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 1582), (6-chloro-pyridin-3-yl methyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Pyridine-2-base]-amine (P-1597), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine- 2-yl]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1598), (6-chloro-pyridin-3-yl methyl)-[5-(chloro-1H-of 5- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-amine (P-1607), [5-(5-chloro-1H-pyrrolo-[2, 3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1608), [5- (5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(2-methoxv-pyridine-3-Ji Jia Base)-amine (P-1609), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyrimidine-2-base]-amine (P-1630), (5-fluoro-pyridin-3-yl methyl)-[5-(5-fluoro-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1631), (6-chloro-pyridin-3-yl methyl)-[5-(5-fluoro-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1632), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5- (5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-1633), [5-(5-fluoro-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-1634), [5-(5- Fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P- 1635), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(6-trifluoromethylpyridin-3- Ylmethyl)-amine (P-1636), [5-(5-fluoro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(2-methoxy Base-pyridin-3-yl methyl)-amine (P-1637), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)- Pyridine-2-base]-(5-fluoro-pyridin-3-yl methyl)-amine (P-1727), (6-chloro-pyridin-3-yl methyl)-[6-fluoro-5-(4-first Base-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-amine (P-1728), (5-fluoro-2-methoxv-pyridine- 3-ylmethyl)-[the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-amine (P- 1729), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-(4-trifluoromethyl- Pyridin-3-yl methyl)-amine (P-1730), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyrrole Pyridine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-1731), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] Pyrimidine-5-ylmethyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-1732), (5-fluoro-6-methoxy Base-pyridin-3-yl methyl)-[the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]- Amine (P-1733), [the fluoro-5-of 6-(4-methyl-7H-pyrrolo-[2,3-d] pyrimidine-5-ylmethyl)-pyridine-2-base]-(2-methoxy Base-pyridin-3-yl methyl)-amine (P-1734), (the chloro-benzyl of 2-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-amine (P-2035), (the chloro-benzyl of 2-)-[5-(4-methoxyl group-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2036), (the chloro-benzyl of 4-)-[the fluoro-5-of 6-(4-methoxyl group-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2037), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyrimidine-2-base]-(6-methoxv-pyridine-3-ylmethyl)-amine (P-2038), (5-fluoro-6-methoxv-pyridine-3- Ylmethyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2040), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-amine (P-2042), [the fluoro-5-of 6-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2043), (5-chloro-pyridine-2-ylmethyl)-[6- Fluoro-5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2044), [6-fluoro-5-(1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2045), (the chloro-pyrrole of 5- Pyridine-2-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P- 2047), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-2048), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2049), (the chloro-benzyl of 4-)-[6-fluoro-5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2050), (the chloro-benzyl of 2-)-[fluoro-5-of 6- (5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-amine (P-2051), [the fluoro-5-of 6-(5-methyl- 1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methoxv-pyridine-3-ylmethyl)-amine (P- 2052), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-phonetic Pyridine-2-base]-amine (P-2057), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2- Base]-[(S)-1-(4-fluoro-phenyl)-ethyl]-amine (P-2058), (5-fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5- Methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2061), [the fluoro-5-of 6-(5-methyl isophthalic acid H- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P-2062), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-2063), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-(5-fluoro-2-first Epoxide-pyridin-3-yl methyl)-amine (P-2064), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl first Base)-pyridine-2-base]-(2-methoxv-pyridine-4-ylmethyl)-amine (P-2065), [the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(2-methvl-pyridinium-4-ylmethyl)-amine (P-2067), [5-(5-first Base-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(4-trifluoromethylpyridin-3-ylmethyl)-amine (P- 2070), (5-fluoro-2-methoxv-pyridine-4-ylmethyl)-[the fluoro-5-of 6-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyridine-2-base]-amine (P-2071), (5-fluoro-2-methoxv-pyridine-4-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrroles And [2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2072), (5-fluoro-6-methoxv-pyridine-3-ylmethyl)- [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2073), [5-(the chloro-1H-of 5- Pyrrolo-[2,3-b] pyridin-3-yl methyl)-6-fluoro-pyridine-2-base]-(2-methvl-pyridinium-4-ylmethyl)-amine (P- 2075), (5-fluoro-2-methoxv-pyridine-4-ylmethyl)-[5-(1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyrimidine- 2-yl]-amine (P-2135), (5-fluoro-2-methoxv-pyridine-4-ylmethyl)-[5-(5-methoxyl group-1H-pyrrolo-[2,3-b] Pyridin-3-yl methyl)-pyrimidine-2-base]-amine (P-2136), [3-methoxyl group-5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2143), [5-(5-chloro-1H-pyrrole Cough up also [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2144), [5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-trifluoromethylpyridin-3-Ji Jia Base)-amine (P-2145), [the fluoro-5-of 3-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-pyridine-2-base]-(6- Trifluoromethylpyridin-3-ylmethyl)-amine (P-2146), [the fluoro-5-of 3-(5-methoxyl group-1H-pyrrolo-[2,3-b] pyridine-3- Ylmethyl)-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)-amine (P-2147), [5-(5-chloro-1H-pyrrolo- [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(5-fluoro-2-methoxv-pyridine-3-ylmethyl)-amine (P-2152), (5- Fluoro-2-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazole-2- Base]-amine (P-2153), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6-methoxyl group- Pyridin-3-yl methyl)-amine (P-2154), (6-methoxv-pyridine-3-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3- B] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-2155), 3-{ [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl Methyl)-pyrimidine-2--amino]-methyl-5-fluoro-1-methyl isophthalic acid H-pyridin-2-ones (P-2157), [5-(the chloro-1H-pyrroles of 5- And [2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(2-methoxv-pyridine-3-ylmethyl)-amine (P-2158), (2-first Epoxide-pyridin-3-yl methyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-amine (P-2159), (6-methoxv-pyridine-2-ylmethyl)-[5-(5-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-3-yl methyl)- Thiazol-2-yl]-amine (P-2162), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiazol-2-yl]-(6- Methoxv-pyridine-2-ylmethyl)-amine (P-2163), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-thiophene Azoles-2-base]-(2,6-dimethoxy-pyridin-3-ylmethyl)-amine (P-2164), [5-(5-chloro-1H-pyrrolo-[2,3-b] pyrrole Pyridine-3-ylmethyl)-6-fluoro-pyridine-2-base]-(5-fluoro-6-methoxv-pyridine-3-ylmethyl)-amine (P-2165) and [5-(5- Chloro-1H-pyrrolo-[2,3-b] pyridin-3-yl methyl)-3-fluoro-pyridine-2-base]-(6-trifluoromethylpyridin-3-ylmethyl)- Amine (P-2172).
Following table shows in step 1 to provide 1H-pyrrolo-[2, the 3-b] pyridine of desired compound (the 4th row) Compound (the 2nd row) and aldehyde compound (the 3rd row).Compound number provides in arranging the 1st, and the quality observed is at the 5th row In.
Embodiment 26: compound form and preparation
Compound disclosed herein can be prepared such as polymorph, salt form and complex in other forms.This solid Form can improve bio-pharmaceutical character further, and can be formulated to further strengthen bio-pharmaceutical character.Such as, the present invention Compound forms acid-addition salts example hydrochloric acid salt or toluene fulfonate or forms the complex with polyprotic acid such as citric acid, it is preferable that Wherein complex is substantially unbodied.This amorphous complex can also add polymer such as HPMCAS, and it is further Stable amorphous form processes.Method may also comprise the spray drying of material.By compound dissolution in 400-500mL Acetone in and with stirring and heating be injected towards in the 1 equivalent citric acid being dissolved in ethanol.It is spray-dried this solution To provide the complex being dried.Add compound/citrate complex to polymer with the identical ratio of acetone/ethanol, join Make other material, such as use HPMCAS orL100-55 and the mixture of poloxamer188.At a sample In, with 40-50% compound, 15-25% citric acid, 25-35%LI 00-55 and 1-10% poloxamer188 Weight ratio binding component.In a sample, with 40-50% compound, 15-25% citric acid and 30-40%HPMCAS Weight ratio binding component.The complex obtained or the amorphous property of the preparation of complex can be composed by X-ray powder diffraction Figure (XRPD), infrared spectrometry and differential scanning calorimetry determine.Such as, the ShimadzuXRD-utilizing Cu Ka to radiate is used 6000X-ray powder diffractometer.Voltage and the amperage of electron tube are respectively set at 40kV and 40mA.Dissipate and scatter Slit is set as 1 ° and receives slit and be set as 0.15mm.Diffraction is irradiated and is detected by Nal scintillation detector. θ-2 θ is used to scan continuously under 3 °/minute (0.4 second/0.02 ° step) from 2.5 ° to 40 ° of 2 θ.Silicon standard substance are analyzed to check Instrument alignment.Data are collected and use XRD-6100/7000v.5.0 to analyze.By being put into by sample, there is silicon insert In aluminum holder, sample is prepared to be analyzed.DSC is used for showing, complex does not has feature phase transformation (characteristic Transition) and it had been completely melt before any free alkali (free base) crystalline transition, has supported these further Complex is unbodied.
Embodiment 27: compound property
Although compound to Fms, Flt-3 and Kit kinase whose any one inhibitory activity for they treatment disease in Activity be important, but compound described herein shows the good character providing advantage as medicine equally.At some In situation, provide the preferred activity for treating some disease relative to Kit and other kinase whose Fms selectivity, such as class wind Wet arthritis, Alzheimer, parkinson, osteoarthritis, glomerulonephritis, interstitial nephritis, lupus nephritis, Renal tubular necrosis, diabetic nephropathy or renal hypertrophy.In some cases, this compound of Fms selective binding of compound is not Can effectively pass through blood brain barrier and provide the preferred activity for treating some disease, such as osteoarthritis, glomerulonephritis, interstitial Property nephritis, lupus nephritis, renal tubular necrosis, diabetic nephropathy or renal hypertrophy.In some cases, the Fms choosing of compound Selecting property combines this compound and can effectively pass through blood brain barrier and provide the preferred activity for treating some disease, such as rheumatoid Arthritis, Alzheimer or parkinson.In some cases, dual Fms/Kit activity provides for treating The preferred activity of some disease, metastatic breast cancer, carcinoma of prostate, multiple myeloma, melanoma, acute myelocytic are white Disorders of blood, brain metastes, neurofibroma, gastrointestinal stromal tumor, rheumatoid arthritis or multiple sclerosis.In some cases, Dual Fms/Flt-3 activity provides the preferred activity for treating some disease, such as acute myeloid leukemia.Except Biochemistry and mensuration based on cell indicate Fms, Kit, Flt-3 or at least Fms and Kit or at least Fms and Flt-3 Kinase inhibiting activity, compound also have the dissolubility of raising, the pharmacokinetic property of improvement and low Cyp suppression.? The available following mensuration of those skilled in the art or similar mensuration assess compound.
The mensuration of biochemistry and activity based on cell is as known in the art, such as, and U.S. Patent Application Publication Number 2009/0076046, because it relates to this kind of mensuration, the disclosure of which is incorporated herein by.In one measures, with regard to c- The suppression of Kit kinase activity, measures chemical-biological activities IC50Value, wherein peptide substrates phosphorylation suppresses as compound concentration Function mensuration.Compound dissolution to be measured reaches the concentration of 20mM in DMSO.These dilute the DMSO of 30 μ L to 120 μ L (4mM) and by 1 μ L add in assay plate.Then, these serial dilutions 1: 2 (50 μ L to 100 μ L DMSO), totally 8 points. Preparing flat board makes each kinase reaction be 1 times of kinase buffer liquid (25mM HEPES, pH 7.5,2mM MgCl2, 2mM MnCl2, 0.01%Tween-20,1mM DTT, 0.01%BSA) in 20 μ L, 5%DMSO and 100 μMs of ATP.Substrate is that 30nM is biological Element-(E4Y) 10 (Millipore).C-kit kinases (is obtained or such as U.S. Patent Application Publication by Millipore (#14-559) Preparation described in number 2009/0076046, because this application relates to this kind of mensuration, the disclosure of which is incorporated herein by) be Each sample 0.75ng.At room temperature incubation kinase reaction is after 1 hour, addition stop buffer (25mM Hepes pH 7.5, 100mM EDTA, 0.01%BSA) in donor bead (the coated pearl of Streptavidin (the Perkin Elmer Life of 5 μ L Science) final concentration 10 μ g/mL)), sample is mixed and at room temperature incubation 20 minutes, is subsequently adding in stop buffer The acceptor bead (the coated pearl of PY20 (Perkin Elmer Life Science) final concentration 10 μ g/mL) of 5 μ L.Sample is in room temperature Lower incubation 60 minutes and read the signal in each hole on Envision reader.Phosphorylated substrate causes the knot of PY20 antibody Merge and cause being connected of donor and acceptor bead so that signal is relevant to kinase activity.Compound concentration curve is used for surveying by signal Determine IC50。
In one measures, with regard to the suppression of Fms kinase activity, measure chemical-biological activities IC50Value, wherein peptide substrates phosphoric acid Change the suppression function mensuration as compound concentration.The testing compound being dissolved in DMSO (1 μ L) is injected towards white 384- In orifice plate (Costar#3705).Fms kinases (Invitrogen#PV3249), biotin-(E4Y)10Substrate (Upstate Biotech, Cat#12-440) and the working stock (Working stocks) of ATP (Sigma, Cat#A-3377) at 25mM Hepes pH 7.5、0.5mM MgCl2、2mM MnCl2, prepared by 2mM DTT, 0.01%BSA and 0.01%Tween-20.Institute Component is had to be injected towards in 384-orifice plate, 1ng/ hole Fms, 30nM biotin-(E4Y) in final concentration of 20 μ L volumes10 (Upstate Biotechnology) and 100 μMs of ATP.Each sample is under 5%DMSO.Then Incubate plates 20 at 30 DEG C Minute.The most before use, from AlphaScreen's PY20Detection Kit (PerkinElmer, Cat#676601M) The working stock of donor bead and acceptor bead, at 25mM Hepes pH 7.5, pH 7.4, is made in 100mM EDTA, 0.01%BSA Standby.In order to terminate reaction, in the dark open flat board and the donor bead solution (Streptavidin pearl) of 5 μ L is added to each hole In.Flat board at room temperature incubation 20 minutes.Then the acceptor bead solution (the coated pearl of PY20) of five microlitres is added to each hole In.The final concentration of each pearl is 10 μ g/mL.Flat board at room temperature incubation 60 minutes.Fluorescence signal is on Envision reader Record.Phosphorylated substrate causes being connected of the combination of PY20 antibody and donor bead and acceptor bead so that signal has with kinase activity Close.Compound concentration curve is used for measuring IC by signal50。
In one measures, with regard to the suppression of Flt-3 kinase activity, measure chemical-biological activities IC50Value, wherein peptide substrates phosphorus Acidifying suppression is as the function mensuration of compound concentration.The testing compound being dissolved in DMSO (1 μ L) is injected towards white 384- In orifice plate (Costar#3705).Flt-3 kinases (Invitrogen), biotin-(E4Y)10Substrate (Upstate Biotech, And the working stock of ATP (Sigma, Cat#A-3377) is at 25mM Hepes pH 7.5,5mM MgCl Cat#12-440)2、5mM MnCl2, prepared by 1mM DTT and 0.01%Tween-20.All components is injected towards in 384-orifice plate, final concentration of 20 μ L bodies 1ng/ hole Flt-3,30nM biotin-(E4Y) in long-pending10With 100 μMs of ATP.Each sample is under 5%DMSO.Then flat board is in room The lower incubation of temperature 1 hour.The most before use, from AlphaScreen PY20Detection Kit (PerkinElmer, Cat# Donor bead 676601M) and the working stock of acceptor bead at 25mM Hepes pH 7.5, pH 7.4,100mM EDTA, 0.3% Prepared by BSA.In order to terminate reaction, in the dark open flat board and the donor bead solution (Streptavidin pearl) of 5 μ L is added extremely In each hole.Flat board at room temperature incubation 20 minutes.Then the acceptor bead solution (the coated pearl of PY20) of five microlitres is added extremely In each hole.The final concentration of each pearl is 10 μ g/mL.Flat board at room temperature incubation 60 minutes.Fluorescence signal is read at Envision Record on number device.Phosphorylated substrate causes being connected of the combination of PY20 antibody and donor bead and acceptor bead so that signal and kinases Activity is relevant.Compound concentration curve is used for measuring IC by signal50。
Compound is assessed in multiple mensuration based on cell.Such as, BCR-FMS/BaF3, BCR-KIT/BaF3, M- NFS-60, M-07e and BAC1.2F5 cell proliferating determining is for assessing the inhibitory activity of Fms or Kit, and MV-4-11 cell increases Grow mensuration for the inhibitory activity assessing in Flt-3.Reagent and evaluation condition are as follows:
BCR-FMS/BaF3 and BCR-KIT/BaF3 cell:
It is saved in the RPMI containing 10%FBS, 1%PenStrep, 1%NEAA and 1%L-glutamine, supplements 1mg/ ML G418 and 5%WEHI-CM (or restructuring Mus IL-3).
Converge every 3-4 days of cell by 1: 50 to 1: 100 points of biographies (split).
M-NFS-60 cell (ATCC#CRL-1838):
It is saved in the RPMI containing 10%FBS, 1%Hepes, 1% Sodium Pyruvate and 0.45% glucose, supplements 62ng/mL Mus M-CSF.
Converge every 3-4 days of cell by 1: 20 point of biography.
M-07e cell (DSMZ#ACC 104):
It is saved in the IMDM containing 10%FBS, supplements the SCF (R&D of people SCF or the 75ng/ μ L of 200ng/mL Systems 255-SC)。
Converge every 3-4 days of cell by 1: 5 to 1: 10 points of biographies.
BAC1.2F5 cell:
It is saved in the α-MEM containing 10% new-born calf serum (Invitrogen#26010-074), supplements 36ng/mL's Mus M-CSF.
Converge every 3-4 days of cell by 1: 4 point of biography.
MV-4-11 cell:
It is saved in Iscove ' s improvement Dulbecco ' the s culture medium containing 10%FBS.
Converge every 3-4 days of cell by 1: 4 point of biography.
First day, count cell, be then centrifuged 5 minutes under 1000rpm in conical tube.Remove supernatant and make as follows Cell settling flux:
BCR-FMS/BaF3 and BCR-KIT/BaF3: in growth medium+1mg/mL G418 (not having WEHI/IL-3) Settling flux is to 2 × 105Individual cell/mL.
M-NFS-60: settling flux is to 5 × 10 in growth medium+62ng/mL Mus M-CSF5Individual cell/mL.
M-07e: settling flux is to 5 × 10 in growth medium+200ng/mL people SCF5Individual cell/mL.
BAC1.2F5: settling flux is to 1.4 × 10 in growth medium+36ng/mL Mus M-CSF5Individual cell/mL.
MV-4-11: settling flux is to 5 × 10 in growth medium+10%FBS5Individual cell/mL.
By plating cells (50 μ L) in each hole of 96-orifice plate (Corning 3610), and at 5%CO at 37 DEG C2 In be incubated overnight, bed board cell is to following final concentration of cells:
BCR-FMS/BaF3 and BCR-KIT/BaF3: 10,000, each hole cell.
M-NFS-60: 25,000, each hole cell.
M-07e: 25,000, each hole cell.
BAC1.2F5: 7,000, each hole cell.
MV-4-11: 25,000, each hole cell.
Second day, the compound under the Cmax of 5mM, by 1: 3 serial dilution, for being total up to the titration of 8, was used DMSO is as comparison.1 μ L aliquot of each dilution point is added in 249 μ L growth mediums and 50 μ L add to containing In the hole of cell, it is provided that 10 μMs of compounds of maximum concentration site.By cell at 37 DEG C at 5%CO2Middle incubation 3 days.
5th day, make ATPlite 1 step luminescence assays system (Perkin Elmer#6016739) and cell culture one Rise and reach room temperature.Following ATPlite is added in each hole:
BCR-FMS/BaF3 and BCR-KIT/BaF3: each hole 25 μ L.
M-NFS-60: each hole 25 μ L.
M-07e: each hole 40 μ L.
BAC1.2F5: each hole 50 μ L.
MV-4-11: each hole 40 μ L.
Cell at room temperature incubation 10 minutes, then read luminescence on Safire reader.Measure luminous directly with Cell number associates, in order to the reading as the function of compound concentration is used for measuring IC50Value.
Further, differentiation of osteoclast measures for assessing Fms inhibitor for treating the merit of osteopathia such as osteoarthritis Effect.At the 0th day, (Lonza catalog number (Cat.No.) PT-8001, containing culture fluid, FBS, L-glutamy for Osteoclast culture base BulletKit Amine, PenStrep, RANKL and M-CSF) culture medium be melted and from the FBS of this test kit, L-glutaminate and PenStrep is injected towards in the osteoclast precursor basal medium of 100mL to provide osteoclast precursor growth medium (OPGM).This culture medium is warmed to 37 DEG C.Osteoclast precursor cells (Lonza catalog number (Cat.No.) 2T-110) freezing in cryovial In being warmed to 37 DEG C and being transferred to the conical tube of 50mL.Cryovial OPGM rinses and is added dropwise to cell along with rotating In conical tube, it is subsequently adding OPGM and volume is adjusted to 20-30mL.Cell is at room temperature centrifuged 15 minutes with 200 × g and will The supernatant of about 3mL moves in new conical pipe.Cell is suspended in remaining supernatant and dropwise adds along with rotating Enter OPGM to adjust volume to 10-15mL.Cell is at room temperature centrifuged 15 minutes with 200 × g and removes the most about 1mL's Supernatant.Cell is again suspended in remaining supernatant, is counted, and adjusts volume to provide big with the OPGM of suitable amount About 1 × 105Individual cell/mL.The 0.1mL aliquot of cell is injected towards in each hole of 96-orifice plate.Testing compound exists In DMSO, preparation is for bed board, 8: 1: 3 serial dilutions under the high concentration of 2.5mM.The 1 μ L etc. of every kind of diluted chemical compound liquid Branch divides and is injected towards in polypropylene board at the bottom of 96 hole V-shapeds, and the OPGM of 0.124mL is injected towards compound.Then in OPGM The compound of 50 μ L is injected towards in the osteoclast precursor cells in 96-orifice plate (providing the highest test concentrations of 5 μMs).From The RANKL (2 μ g) of BulletKit reconstructs in the OPGM of 1mL, and vortex stirs and is centrifuged the most momently.The 792 μ L of RANKL Aliquot is injected towards in the OPGM of 6mL and 50 μ L are injected towards in shallow control wells.Then from BulletKit's The M-CSF (10 μ g/mL) of 76.6 μ L is injected towards remaining 5.8mL OPGM/RANKL solution (4X RANKL/M-C SF/ OPGM) in.50 μ L aliquots of this solution are injected towards in remaining hole, and residue stores for future use at 4 DEG C.Flat Plate is incubation 6 days at 37 DEG C, and the most remaining OPGM/RANKL/M-CSF solution is warmed to 37 DEG C.Remaining about 198 μ L Be combined with the OPGM of 6mL.From osteoclast hole, the RANKL/OPGM of Aspirate culture media and 100 μ L is injected towards shallow comparison In.Remaining RANKL/OPGM is combined with residue M-CSF of about 18.5 μ L.From the 0th day remaining 4X RANKL/M-CSF/ OPGM is diluted 1 times and is combined with the solution of fresh preparation.The 0.1mL aliquot of this solution is injected towards each osteoclast In hole and 37 DEG C of incubations 1 day.Acid phosphatase kit (Cayman Chemical catalog number (Cat.No.) 10008051) is warmed to room Temperature.Measure the water dilution of buffer 5mL 45mL.For each flat board, two substrate sheets are dissolved in the mensuration buffer of 4.5mL In, mix to smash sheet by eddy current.The water dilution of stop buffer 12mL 36mL.In tissue culture covers, 20 μ L's is each broken The supernatant in osteocyte hole is transferred in 96 orifice plates.30 μ L aliquots of substrate solution are injected towards in each hole and 37 Incubation 20 minutes at DEG C, are subsequently adding in 100 μ L stop buffers extremely each hole.The absorptance in each hole is at Safire plate reader On under 405nM read.Absorbance readings to plotted against concentration with provide every kind of compound IC50。
Following table shows Fms and the Kit biochemistry inhibitory activity according to shown exemplary compounds of the present invention and selection Property (Kit IC50/FmsIC50) and inhibitory activity selectivity (Kit based on BCR-FMS/BaF3 and BCR-KIT/BaF3 cell IC50/FmsIC50):
Following table show Fms and the Flt-3 biochemistry inhibitory activity according to exemplary compounds of the present invention and based on The inhibitory activity of BCR-FMS/BaF3 and MV-4-11 cell, described compound is the Approximate Equivalent suppression of shown Fms/Flt-3 Agent:
Differentiation of osteoclast measure in, compound P-1554, P-2001, P-2003, P-2004, P-2019, P-2028, P-2029、P-2030、P-2031、P-2032、P-2037、P-2038、P-2045、P-2048、P-2049、P-2052、P-2057、 P-2061, P-2063, P-2064, P-2070, P-2146, P-2147, P-2157, P-2165, P-2176 and P-2193 show Less than the IC of 0.1 μM50。
As the instruction of relative solubility, have evaluated compound turbidity in aqueous.For assessment at different physiology Compound property possible in compartment such as stomach, intestinal and blood, employs a series of aqueous buffer solution with different pH.From And, every kind of diluted chemical compound is four different physiology relevant buffers and passes through metric measurement solution turbidity.Logical Cross formed abundant insoluble suspension with under three kinds of wavelength (490,535 and 650nm) improve average optical to 0.01 with On measure the compound concentration of turbidity for being defined on the solubility limit of compound in this buffer.
Compound is dissolved in dimethyl sulfoxide with the concentration of 25mM, during then 1: 1 serial dilution enters 96 orifice plates, pure two Diluting 10 times in methyl sulfoxide, the final hole often arranged is that dimethyl sulfoxide is blank.In assay plate, by 99 bufferings suitable for μ L Liquid adds in each hole, and adds in buffer by each diluted sample thing of 1 μ L, it is thus achieved that at the water with different PH Final total concentration scope in solution.The buffer used is: simulated gastric fluid (SGF-pH1.5) 0.5M NaCl, pH 1.5；Mould Intend intestinal juice (SIF-pH 4.5 and pH 6.8) 0.05M NaH2PO4, pH 4.5 and 6.8 and Hepes buffer (HEPES-pH 7.4) 10mM HEPES、150mM NaCl、pH 7.4.Also have evaluated control compound pyrene, estriol and phloride.Rotating Plates And then mix 1 minute, and use Tecan Safire II to read absorbance, read visible with four positions in each hole Wavelength in district (490,535 and 650nm), the turbidity that its reflection exists.It is plotted in the average light of each wavelength in each hole close The degree figure to compound concentration, for each wavelength, concentration when curve crosses threshold value 0.01O.D. is reported as terminal turbidity and surveys Determine result.The meansigma methods of three wavelength is for the turbidity of comparative compound.If threshold concentration ＜ 31.3 μMs, it is believed that compound has There is low dissolubility；If threshold concentration is 31.3 μMs to 250 μMs, it is believed that compound has medium dissolubility；If threshold value is dense Degree is ＞ 250 μMs, it is believed that compound has high dissolubility.
Following table shows under each pH based on phase according to exemplary compounds of the present invention shown in turbidity threshold concentration To dissolubility (L=is low, M=is medium, H=high):
CYP (Cytochrome P450) enzyme is key agents metabolic enzyme present in the liver.Determine compound CYP enzymatic activity (the IC of each of CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4 (BFC) and CYP3A4 (BQ)50) Suppression, the suppression of the most known substrate utilization causes the fluorescence of metabolite to reduce.Monitoring is as compound concentration function Product fluorescence.
Compound being dissolved in DMSO to concentration is 100mM.These 1 μ L are diluted in the acetonitrile of 82 μ L.Then by this solution 11 μ L aliquots add to 204 μ L cofactor mixture (1.3%NADPHz regenerative system solution A, from BD 1.04%NADPH regenerative system solution B, 5% acetonitrile and the 0.05%DMSO of Biosciences) in.These then serial dilutions 1: 1 (160 μ L are than 160 μ L cofactor mixture), totally 10 points.10 μ L aliquots of this final mixture are reallocated into 384 Incubation 10 minutes in the assay plate of hole and at 37 DEG C.By enzyme and substrate mixture (10 μ L；0.5pmol CYP1A2/5μM CEC；1.0pmol CYP2C9/75μM MFC；0.5pmol CYP2C19/25μM CEC；1.5pmol CYP2D6/1.5μMΛ MMC；1.0pmol CYP3A4/50μM BFC；Or CYP3A4/40 μM of BQ of 1.0pmol) add in these assay plates.Will Assay plate is incubation (CYP1A2-15 minute at 37 DEG C；CYP2C9-45 minute；CYP2C19,2D6 and 3A4-30 minute) and Tecan Safire 2 plate reader (CYP1A2,2C19 and 3A4 409ex/460em；CYP2C9 and 2D6 409ex/ 530em) upper reading.Compound concentration figure is used for measuring IC by signal50.The enzyme of this mensuration and substrate are available from BD Biosciences.Although other factors relates to measuring CYP effect in vivo, but compound preferably has the IC of ＞ 5 μMs50Value, more Preferably there is the IC of ＞ 10 μMs50Value.
Following table shows that the Cyp of the shown exemplary compounds according to the present invention suppresses:
In male Sprague Dawley rat or male Beagle dog, have evaluated compound (include its any solid shape Formula or preparation) pharmacokinetic property.The IV of the jugular vein conduit by implanting via surgical operation injects or by oral Raise by force (PO), per diem take compound to rat.The 20mg/mL stock solution that every kind of compound is prepared as in dimethyl sulfoxide, will Dilution is to provide the administration stock solution under expectation concentration further, for IV or PO preparation for it.IV is administered, stock solution will be administered It is diluted toEthanol: 1: 1: 8 mixture of water.PO is administered, administration stock solution is diluted to 1% methylcellulose In.In box-packed form (or every kind of compound, its solid form or its preparation are carried out respectively), IV is administered, each chemical combination Thing is diluted to 0.5mg/mL, is administered for PO, and each diluted chemical compound is 0.4mg/mL, and respectively with 1mg/kg (2mL/kg) Or 2mg/kg (5mL/kg) is administered.The animal that IV is administered, 5,15,30 and 60 minutes after being given daily and 4,8 and 24 hours, collect tail vein liquid sample with lithium heparin anti-coagulating agent.The animal that PO is administered, 30 points after being given daily Clock, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours, collect tail vein liquid sample with lithium heparin anti-coagulating agent.By closing The oral capsule of suitable preparation, is administered to dog with 50mg/mL every day.After being given daily 30 minutes, 1 hour, 2 hours, 4 little Time, 8 hours and 24 hours, with lithium heparin anti-coagulating agent collect cephalic vein blood sample.All of sample is treated to blood plasma also Freezing, for being analyzed every kind of compound later by LC/MS/MS.Draw the figure of the blood plasma level as time function, With assessment AUC (ng*hr/mL).Compound according to the present invention preferably demonstrates the improvement relative to previously described compound Pharmacokinetic property, i.e. relative to previously described compound, they have significantly higher AUC, CmaxWith the half-life one Plant or multiple value.
Compound can be assessed similarly and penetrate into the analysis in brain.Every kind of compound is prepared as in dimethyl sulfoxide 100mg/mL stock solution, and the atenolol of control compound 100mg/mL and the phenazone of 50mg/mL.With box-like formula, extremely Many three test compounds, together with atenolol and phenazone, combine with each 180 μ L, and add 1% first to 17.1mL In base cellulose.Compound is form of suspension, and it gives 2 groups with single dose (every kg body weight 10mL) form by oral raising by force CD rat (8-9 week, often organize n=3), rat of other group is given only carrier.The rat of one group of compound treatment is upon administration Within 2 hours, be killed, other group was killed at 6 hours.Collect blood plasma with lithium heparin and collect brain, being cut to right hemisphere and a left side Hemisphere, weighs and quick-freezing.Use has 96 hole equilibrium dialysis equipment (The of 5K MW mwco membrane (cut off membrane) Nest Group, Inc.), according to the scheme of supplier, by equilibrium dialysis assessment brains (30%) and plasma sample, in dialysis Film side is sample and is 1 × PBS of same volume at opposite side.This equipment plate vibrator (The Nest Group, Inc.) it is incubated overnight at 37 DEG C on.Compound concentration in both sides is analyzed to calculate mass balance by LC/MS/MS and is reclaimed Rate (mass balance recovery).The standard curve produced for every kind of compound is used to calculate the concentration in PBS side. PBS concentration is free cpds concentration, and the side with biological sample provides the concentration in blood plasma and brain.
The further feature of complex can be used for the performance that display improves, the essentially amorphous citric acid of such as similar preparation The intrinsic rate of dissolution of salt composite or its preparation with in the simulated gastric fluid (SGF) do not have enzyme and in simulated intestinal fluid (SIF) The intrinsic rate of dissolution of the crystal form of compound or its similar formulations is compared.The bead of test sample is dissolved in suitably stream In body, and under 254nm (SGF) or 310nm (SIF), measure the UV absorptance as time function and draw.
Embodiment 28: In vivo model system test
For internal test, suitable animal model system can be chosen to use.Such as, for multiple sclerosis, logical Often use Rodents experiment allergic encephalitis (EAE) system.This system such as at Steinman, 1996, Cell 85: 299-302 and Secor etc., are described in 2000, J Exp.Med5:813-821, and it is incorporated in their entirety this Literary composition.Arthritis (ClA) that rheumatoid arthritis (RA), II Collagen Type VI are caused, the meiofauna of rheumatoid arthritis (RA) Model can be used for testing.This model such as at Current Rheumatology Reviews such as Wooley, 2008,4:277- Being described in 287, it is incorporated in their entirety herein.
Similarly, other model system can be used for assessing compound as herein described.Many compounds as herein described, its Compound (such as P-1496, P-1622, P-1669, P-1679, the P-of ', IIa, III and III ' including Formulas I, I ', II, II 2001、P-2028、P-2029、P-2030、P-2038、P-2043、P-2045、P-2048、P-2049、P-2052、P-2057、P- 2061、P-2062、P-2063、P-2064、P-2067、P-2070、P-2071、P-2073、P-2075、P-2078、P-2088、P- 2097、P-2103、P-2118、P-2139、P-2157、P-2165、P-2176、P-2193、P-1554、P-1562、P-2003、P- 2004、P-2008、P-2013、P-2019、P-2031、P-2032、P-2037、P-2079、P-2081、P-2082、P-2131、P- 2146、P-2147、P-2148、P-2154、P-2163、P-2172、P-2198、P-2202、P-1644、P-1646、P-1667、P- 2003、P-2004、P-2009、P-2019、P-2029、P-2030、P-2031、P-2032、P-2034、P-2037、P-2038、P- 2040, P-2041, P-2044, P-2047, P-2048, P-2050, P-2057 and P-2065；Paragraph [0038], [0079], [0094], the compound disclosed in [0102], [0103] and [0104]；And the compound described in embodiment) or a combination thereof Thing, its hydrate or its solvate are tested in mice and are used for treating various disease as herein described and disease.
Rheumatoid arthritis (RA) mouse model that collagen causes.
Method: intradermal injection collagen-CFA, advanced collagen at 21 days by peritoneum (ip) injection subsequently, and this is multiple mice Strain, especially for the DBA/1 genotype in this research causes rheumatoid arthritis (Brand etc., 2004；Wooley etc., 1981).Use the grade of every pawl 0-4, given a mark by clinic, quantitatively and record disease.Mark have recorded in each toes and pass Swelling and rubescent degree and scope in joint, and do not use each fore paw or after grab in the case of culminate.Every is moved Thing running summary of the points scored, produces largest score 16, and it shows that animal avoids using all pawls.After primary immune the 21st day, when for When the average clinical scores of all animals is 2.5, the Disease Score of each group reaches balance.Treatment is carried out 21 days, with following administration group Every day oral administration: carrier, and the compounds of this invention of 10mg/kg, 20mg/kg and 50mg/kg.
Result
The oral administration of the compounds of this invention inhibits clinical disease in muroid ClA model to send out with dose-dependent form Exhibition, has notable reaction under the dosage (10,20 and 50mg/kg qd) of all tests.The histopathological analysis in joint shows Show, inhibit inflammation, bone resorption, cartilage lesions and pannus to be formed by the treatment of the compounds of this invention.The compounds of this invention Mechanism of action by joint reduce macrophage and osteoclast mark be confirmed.
Compare with vehicle Control, Fms inhibitors of kinases as herein described every day oral administration at all proof load water Quick benefit is shown, such as the clinical scores confirmation by reducing, the clinical scores of reduction under flat (10,20and 50mg/kg) Reflect the less swelling of limbs and rubescent.This clinical benefit is formed and osseous tissue by the inflammation reduced, cartilage lesions, pannus The histopathological score destroyed is confirmed.In joint tissue, the mark of macrophage and osteoclast reduces, and this confirms this The binding mode of the described compound of literary composition is by suppression Fms receptor tyrosine kinase, its for these cytophyletic propagation and Differentiation it is critical that.The plasma concentration of the administration group of the time point extraction of 2 hours shows dosage clearly upon administration Ratio responds.
The all patents quoted in this specification and other list of references represent those skilled in the art in the invention's Level, and be integrally incorporated herein with it by quoting, including any table and figure, the degree being incorporated to is such as each list of references It is integrally incorporated herein with it individually through quoting.
Those skilled in the art should readily appreciate that the present invention is very suitable for obtaining the result being previously mentioned and advantage, And the most intrinsic result and advantage.Method described herein, change and the compositions preferably represented at present It is exemplary, is not intended to become limitation of the scope of the invention.Those skilled in the art it is appreciated that change therein and its Its application, this comprises within the spirit of the invention, and the scope such as claims limits.
The invention the most illustratively described can be to lack either element not specifically disclosed herein the most Implement in the case of element, restriction perhaps many restrictions.So that it takes up a position, for example, under each instance herein, term " includes (comprising) ", " substantially by ... composition (consisting estentially of) " and " by ... form (consisting of) " in any one can replace with other two terms.Therefore, for using the basis of a kind of term Invention embodiment, the present invention also includes other embodiment, and wherein the one in these terms can be by these terms In another kind substituted.In each embodiment, term has they fixed implications.It is therefoie, for example, it is a kind of real The mode of executing can include the method for " comprising " series of steps, and another embodiment can include " substantially by same steps group Become " method, and the method that the third embodiment can include " being made up of same steps ".The term used and statement conduct Descriptive term rather than limited term use, and are not intended to when using these terms and statement get rid of display and retouch The feature stated or any equivalent of its part, and it is to recognize that various amendments are possible in the range of claimed invention 's.Although it should therefore be understood that the present invention is disclosed particularly by preferred embodiment and optional feature, but this Concept disclosed herein can be modified and change by skilled person, and these modifications and variations are contemplated as falling with this Within the scope of invention, as defined by the appended claims.
Additionally, when inventive feature or aspect are described according to marlcush group or other optional group, this area skill Art personnel it will be appreciated that the present invention thus be also according to this marlcush group other group any separate member or subgroup member enter Line description.
Meanwhile, without indicating on the contrary, when providing each numerical value for embodiment, by using two different values to make For the end points of scope, describe other embodiment.Such scope is also contained in the range of described invention.
Therefore, other embodiment comprise within the scope of the present invention with claims in the range of.

Claims (22)

1. there is Formula II ' compound:
Or its salt, tautomer or stereoisomer,
Wherein:
R6Selected from methyl ,-C (O)-N (H)-R14With-N (H)-C (O)-R15；
R14It it is low-carbon alkyl；
R15It it is low-carbon alkyl；And
(i)R16It is H, and R17It is-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the lower alkanes of methoxy substitution Base ,-CN or-O-R20；Or
(ii)R17It is H, and R16It is-F ,-Cl ,-Br, low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the lower alkanes of methoxy substitution Base ,-CN or-O-R20；
R18It is-F or-Cl；
R19It is H；And
R20It is low-carbon alkyl, the substituted low-carbon alkyl of fluorine, the low-carbon alkyl of methoxy substitution or cycloalkyl.
2. the compound described in claim 1, wherein R6It is-C (O)-N (H)-R14。
3. the compound described in claim 1, wherein R6It is-N (H)-C (O)-R15。
4. the compound described in claim 1, it has a following formula:
5. the compound described in claim 1, it has a Formula II:
6. the compound described in claim 5, wherein R16It is H, and R17Substituted selected from-F ,-Cl ,-Br, low-carbon alkyl, fluorine Low-carbon alkyl ,-OR20Or the low-carbon alkyl of methoxy substitution；Or R17It is H, and R16Selected from-F ,-Cl ,-Br, low-carbon alkyl, fluorine Substituted low-carbon alkyl ,-OR20Or the low-carbon alkyl of methoxy substitution.
7. the compound described in claim 5, wherein R16It is H, and R17Substituted selected from-F ,-Cl ,-Br, low-carbon alkyl, fluorine Low-carbon alkyl and the low-carbon alkyl of methoxy substitution；Or R17It is H, and R16Replace selected from-F ,-Cl ,-Br, low-carbon alkyl, fluorine Low-carbon alkyl and the low-carbon alkyl of methoxy substitution.
8. the compound described in claim 1, wherein said compound is selected from:
9. the compound described in claim 5, wherein said compound is
10. compositions, it includes the compound described in claim 1 and pharmaceutically acceptable excipient or carrier.
11. test kits, it includes the compound described in claim 1.
12. compositionss, it includes the compound described in claim 8 and pharmaceutically acceptable excipient or carrier.
13. compositionss, it includes the compound described in claim 9 and pharmaceutically acceptable excipient or carrier.
14. treatments suffer from the disease or disease or the method for object that is under disease or disease risk, and described method includes having The compound described in claim 1 of the object effective dose needed, wherein said disease or disease are rheumatoid arthritis and bone Arthritis.
15. treatments suffer from the disease or disease or the method for object that is under disease or disease risk, and described method includes having The compound described in claim 8 of the object effective dose needed, wherein said disease or disease are rheumatoid arthritis and bone Arthritis.
16. treatment suffers from the disease or disease or the method for object that is under disease or disease risk, described method includes having The compound described in claim 9 of the object effective dose needed, wherein said disease or disease are osteoarthritis class and rheumatism Arthritis.
17. prepare Formula II according to claim 1 ' the method for compound, described method includes:
Form Formula II being enough to ' compound under conditions of, with the compound of Formula IV:
The compound of contact Formula VII:
,
Wherein:
P1And P2Each is amido protecting group independently；And
X is H or halogen.
18. formulas:
Compound, or its salt, tautomer or stereoisomer.
19. formulas:
Compound, or its salt, tautomer or stereoisomer.
20. formulas:
Compound, or its salt, tautomer or stereoisomer.
21. formulas:
Compound, or its salt, tautomer or stereoisomer.
22. formulas:
Compound, or its salt, tautomer or stereoisomer.
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